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EVIDENCE AND RESEARCH

 

Here are just a few interesting medical articles/published papers that help establish the role or potential use for the clinical application of (adipose derived) stem cells. This is obviously far from a comprehensive and final list, that is not the intention. It is however a good starting point, showing some of the development history and current thoughts and knowledge. We will endeavour to expand on this information when appropriate articles comes to hand.

We are compiling a list of topics at the top that may help you find relavant information relating more specifically to your problems or interests.  You can select a particular topic from the list of headings, which will then take you  to the first article on that condition. There may be more than one article so scroll down to view.

Not all topics are currently linked to articles. This list of topics and related articles will be extended, and updates made regularly.

 

 

Why Adipose Derived Stem Cells?

Intravenous Stem Cells

Arthritis (eg : osteoarthritis of knee, hip ) 

Asthma

Autism

Autoimmune Disorders (eg : multiple sclerosis,rheumatoid arthritis, SLE, polymyotitis,atopic dermatitis,type 1 diabetes)

COAD,COPD (chronic obstructive airways/pulmonary disease)

Diabetes

Heart Condition

Inflammatory Bowel

Knee Injury ( eg : meniscal tear, torn cartilage)

Multiple Sclerosis

Retinal (eye) problems(eg : macular and retinal degeneration/ dystrophy, retinal detachment, diabetic retinopathy)

Rheumatoid Arthritis

Spinal Cord

Stroke 

Clinical Trials for Mesenchymal Stem Cells



J Long Term Eff Med Implants. 2010;20(3):219-50.

Stem cells: a new paradigm in medical therapeutics.

Source

sadanand.mankikar@gmail.com

Abstract

Even though the stem cells have been studied for decades, only during the past few years has there been an overwhelming proliferation of publications covering isolation, cultivation and utilization of the body's master cells. This paper attempts to summarize the recent studies in the field of stem cells. A number of studies have reported the existence of multipotent stem cells in the cord, cord blood, placenta, bone marrow, brain, heart, teeth, skin, liver, hair follicles and many other tissues and organs, giving rise to cell types other than their tissue of origin. Increased therapeutic use of stem cells has resulted in scientific methods of collection, testing, processing and storage of these cells, with minimal cell damage and differentiation. Cell expansion, bioreactors and tissue engineering are employed extensively to improve the cell dose and outcome. Stem cell infusion, transplantation and implantation are accepted curative therapies for many malignant and non-malignant conditions. Stem cell therapies also provide alternative solutions for the repair and regeneration of various tissues and organs. There has been a dramatic improvement in the understanding of immunosuppressive properties of stem cells on various immune cell types. Stem cells are found to secrete angiogenic cytokines that increase neovascularization. They bring the promise of curing a disease state as these cells normally regenerate tissues in a healthy organism. Stem cell transplantation, in isolation or in combination with other procedures, has been found to be effective. Stem cell therapy is also seen as a possible alternative for the treatment of different diseases such as juvenile diabetes, amyotrophic lateral sclerosis, cerebral palsy, stroke, spinal cord injury and Parkinson's disease. Regenerative medicine using human stem cells is one of the new and promising fields for treating various intractable diseases and damaged organs.


Tissue Eng. 2001 Apr;7(2):211-28.

Multilineage cells from human adipose tissue: implications for cell-based therapies.

Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH.

Source Laboratory for Regenerative Bioengineering and Repair, UCLA School of Medicine, Los Angeles, California, USA.

Abstract

Future cell-based therapies such as tissue engineering will benefit from a source of autologous pluripotent stem cells. For mesodermal tissue engineering, one such source of cells is the bone marrow stroma. The bone marrow compartment contains several cell populations, including mesenchymal stem cells (MSCs) that are capable of differentiating into adipogenic, osteogenic, chondrogenic, and myogenic cells. However, autologous bone marrow procurement has potential limitations. An alternate source of autologous adult stem cells that is obtainable in large quantities, under local anesthesia, with minimal discomfort would be advantageous. In this study, we determined if a population of stem cells could be isolated from human adipose tissue. Human adipose tissue, obtained by suction-assisted lipectomy (i.e., liposuction), was processed to obtain a fibroblast-like population of cells or a processed lipoaspirate (PLA). These PLA cells can be maintained in vitro for extended periods with stable population doubling and low levels of senescence. Immunofluorescence and flow cytometry show that the majority of PLA cells are of mesodermal or mesenchymal origin with low levels of contaminating pericytes, endothelial cells, and smooth muscle cells. Finally, PLA cells differentiate in vitro into adipogenic, chondrogenic, myogenic, and osteogenic cells in the presence of lineage-specific induction factors. In conclusion, the data support the hypothesis that a human lipoaspirate contains multipotent cells and may represent an alternative stem cell source to bone marrow-derived MSCs.


Mol Biol Cell. 2002 Dec;13(12):4279-95.

Human adipose tissue is a source of multipotent stem cells.

Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH. Source Department of Surgery and Orthopedics, Regenerative Bioengineering and Repair Laboratory, UCLA School of Medicine, Los Angeles, California 90095, USA. zukpat@yahoo.com

Abstract

Much of the work conducted on adult stem cells has focused on mesenchymal stem cells (MSCs) found within the bone marrow stroma. Adipose tissue, like bone marrow, is derived from the embryonic mesenchyme and contains a stroma that is easily isolated. Preliminary studies have recently identified a putative stem cell population within the adipose stromal compartment. This cell population, termed processed lipoaspirate (PLA) cells, can be isolated from human lipoaspirates and, like MSCs, differentiate toward the osteogenic, adipogenic, myogenic, and chondrogenic lineages. To confirm whether adipose tissue contains stem cells, the PLA population and multiple clonal isolates were analyzed using several molecular and biochemical approaches. PLA cells expressed multiple CD marker antigens similar to those observed on MSCs. Mesodermal lineage induction of PLA cells and clones resulted in the expression of multiple lineage-specific genes and proteins. Furthermore, biochemical analysis also confirmed lineage-specific activity. In addition to mesodermal capacity, PLA cells and clones differentiated into putative neurogenic cells, exhibiting a neuronal-like morphology and expressing several proteins consistent with the neuronal phenotype. Finally, PLA cells exhibited unique characteristics distinct from those seen in MSCs, including differences in CD marker profile and gene expression.



 

J Nihon Med Sch. 2003 Aug;70(4):300-6.

Mesengenic potential and future clinical perspective of human processed lipoaspirate cells.

Mizuno H, Hyakusoku H.

Source Department of Plastic and Reconstructive Surgery, Nippon Medical School, Tokyo, Japan. hiromzn@attglobal.net

Abstract

The use of stem cells is promising for future cell-based therapy such as tissue regeneration and engineering. Although Embryonic Stem Cells (ESCs) are theoretically highly beneficial, there are some potential limitations of cell regulations and ethical consideration. Mesenchymal Stem Cells (MSCs) isolated from bone marrow stroma have been shown to possess adipogenic, osteogenic, chondrogenic, myogenic and neurogenic potential in vitro. However, bone marrow procurement is severely painful for donors and often requires general anesthesia. Moreover, only small numbers of cells can be harvested. We previously hypothesized that human adipose tissue obtained from liposuction procedures also contains the same cell population as MSCs, because adipose tissue is mesenchymal in origin, like bone marrow stroma. Subsequent studies revealed that: (1) cell population (which we termed Processed Lipoaspirate [PLA] cells), observed by indirect immunofluorescence study of adipose tissue, consist of cells of mesenchymal origin that have little contamination with endothelial cells, smooth muscle cells and pericytes; (2) these PLA cells exhibit low levels of cell senescence even after multiple passage, as demonstrated by beta-galactosidase staining assay; and (3) PLA cells can differentiate into adipogenic, osteogenic, chondrogenic and myogenic cells in vitro in lineage-specific culture media. These findings suggest that human PLA might have a mesodermal stem cell population. Since human adipose tissue is plentiful, easily harvested in large quantity under local anesthesia with little patient discomfort, it may be an alternative stem cell source for mesenchymal tissue regeneration and engineering. This review highlights our previous research work on PLA cells and future clinical perspectives, particularly in the field of plastic and reconstructive surgery.


 

 Tsitologiia. 2006;48(2):83-94.

Adipose stromal cells--plastic type of cells with high therapeutic potential.

Traktuev DO, Parfenova EV, Tkachuk VA, March KL 

Abstract.

Much effort has been made in searching for multipotent cell types with high therapeutic potentials for repair of damaged tissue. Through enzymatic digestion of fat tissue, it is possible to obtain a large number of stromal cells. Isolated cells show a high proliferate capacity in culture. All this makes adipose stromal cells (ASC) promising candidates for their use in cell therapy.


J Atheroscler Thromb. 2006 Apr;13(2):77-81. 

 Adipose tissue-derived stromal cells as a novel option for regenerative cell therapy.

Nakagami H, Morishita R, Maeda K, Kikuchi Y, Ogihara T, Kaneda Y.

Source Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita 565-0871, Osaka, Japan. nakagami@gts.med.osaka-u.ac.jp

Abstract

Adult stem cells hold great promise for use in tissue repair and regeneration, and the delivery of autologous progenitor cells into ischemic tissue is emerging as a novel therapeutic option. We and others have recently demonstrated the potential impact of adipose tissue-derived stromal cells (ADSC) on regenerative cell therapy for ischemic diseases. The main benefit of ADSC is that they can be easily harvested from patients by a simple, minimally invasive method and also easily cultured. Cultured ADSC can be induced to differentiate into not only adipocytes, but also bone, neurons or endothelial cells in certain conditions. Interestingly, they secrete a number of angiogenesis-related cytokines, such as vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), which might be suitable for regenerative cell therapy for ischemic diseases. In the ischemic mouse hindlimb, the angiogenic score was improved in the ADSC-treated group. Moreover, recent reports demonstrated that these ADSC can also be induced to differentiate into cardiac myocytes. These adipose tissue-derived cells have potential in angiogenic cell therapy for ischemic disease, and might be applied for regenerative cell therapy instead of bone marrow cells in the near future.


Pathology. 2011 Oct;43(6):592-604.

Potential therapeutic applications of mesenchymal stromal cells.

Source

Institute of Haematology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.

Abstract

Mesenchymal stromal cells (MSCs) are a non-homogeneous population of plastic-adherent cells which were initially isolated from post-natal bone marrow. They have the capacity to differentiate to multiple mesodermal lineages including bone, cartilage and adipose tissue. In stringent culture conditions, MSCs can also be induced to differentiate into different cell types of endoderm and neuroectoderm lineages. To date, no specific marker identifies MSCs, although a number of cell surface antigens have been described which enrich for MSCs. Mesenchymal stromal cells possess a number of properties which have generated considerable interest in diverse cellular therapeutic applications. The capacity of MSCs to differentiate into multiple different cell lineages has seen them actively explored for tissue repair, particularly in cardiac, orthopaedic and neurological applications. A large body of data indicates that MSCs possess immunomodulatory properties. Mesenchymal stromal cells are immunosuppressive, interacting with T lymphocytes, antigen presenting cells, B lymphocytes, and natural killer cells. In addition, they are immunoprivileged, allowing transplantation across allogeneic barriers. These immunomodulatory properties have seen infusion of MSCs for the treatment of steroid refractory graft versus host disease, a life threatening complication of haemopoietic cell transplantation, with promising results. Furthermore, these immune functions may lead to roles in the facilitation of engraftment, induction of tolerance and as therapy in autoimmune disease.


 

Brain Res. 2010 Jul 9;1343:226-35. Epub 2010 May 12.

Intravenous administration of mesenchymal stem cells derived from bone marrow after contusive spinal cord injury improves functional outcome.

Source

Department of Neurosurgery, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan.

Abstract

Transplantation of mesenchymal stem cells (MSCs) derived from bone marrow has been shown to improve functional outcome in spinal cord injury (SCI). Systemic delivery of MSCs results in therapeutic benefits in a number of experimental central nervous system disorders. In the present study we intravenously administered rat MSCs derived from bone marrow at various time points after induction of a severe contusive SCI in rat to study their therapeutic effects. MSCs were systemically delivered at varied time points (6h to 28 days after SCI). The spinal cords were examined histologically 6 weeks after SCI. Stereological quantification was performed on the spinal cords to determine donor cell (MSCs transduced with the LacZ gene) density in the lesions. Light microscopic examination revealed that cavitation in the contused spinal cords was less in the MSC-treated rats. A limited number of cells derived from MSCs (LacZ(+)) in the injury site expressed neural or glial markers. Functional outcome measurements using the Basso-Beattie-Bresnehan (BBB) score were performed periodically up to 6 weeks post-SCI. Locomotor recovery improvement was greater in the MSC-treated groups than in sham controls with greatest improvement in the earlier post-contusion infusion times. The availability of autologous MSCs in large number and the potential for systemically delivering cells to target lesion areas without neurosurgical intervention suggests the potential utility of intravenous cell delivery as a prospective therapeutic approach in acute and subacute SCI.


Stem Cells Dev. 2011 Aug;20(8):1297-308. Epub 2011 Mar 17.

Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans.

Source

Stem Cell Research Center, RNL Bio Co, Ltd, Seoul, Republic of Korea. jcra@rnl.co.kr

Abstract

Adipose tissue-derived mesenchymal stem cells (AdMSCs) represent an attractive and ethical cell source for stem cell therapy. With the recent demonstration of MSC homing properties, intravenous applications of MSCs to cell-damaged diseases have increased. In the present study, the toxicity and tumorigenicity of human AdMSCs (hAdMSCs) were investigated for clinical application. Culture-expanded hAdMSCs showed the typical appearance, immunophenotype, and differentiation capacity of MSCs, and were genetically stable at least 12 passages in culture. Cells suspended in physiological saline maintained their MSC properties in a cold storage condition for at least 3 days. To test the toxicity of hAdMSCs, different doses of hAdMSCs were injected intravenously into immunodeficient mice, and the mice were observed for 13 weeks. Even at the highest cell dose (2.5×10(8) cells/kg body weight), the SCID mice were viable and had no side effects. A tumorigenicity test was performed in Balb/c-nu nude mice for 26 weeks. Even at the highest cell dose (2×10(8) MSCs/kg), no evidence of tumor development was found. In a human clinical trial, 8 male patients who had suffered a spinal cord injury >12 months previous were intravenously administered autologous hAdMSCs (4×10(8) cells) one time. None of the patients developed any serious adverse events related to hAdMSC transplantation during the 3-month follow-up. In conclusion, the systemic transplantation of hAdMSCs appears to be safe and does not induce tumor development.


Exp Mol Med. 2011 Oct 31;43(10):596-603. doi: 10.3858/emm.2011.43.10.069.

In vitro migration capacity of human adipose tissue-derived mesenchymal stem cells reflects their expression of receptors for chemokines and growth factors.

Source

Stem Cell Research Center RNL BIO Co., Ltd. Seoul, Korea.

Abstract

The homing properties of adipose tissue-derived mesenchymal stem cells (AdMSCs) have stimulated intravenous applications for their use in stem cell therapy. However, the soluble factors and corresponding cellular receptors responsible for inducing chemotaxis of AdMSCs have not yet been reported. In the present study, the migration capacity of human AdMSCs (hAdMSCs) toward various cytokines or growth factors (GFs) and the expression of their receptors were determined. In a conventional migration assay, PDGF-AB, TGF-β1, and TNF-α showed the most effective chemoattractant activity. When AdMSCs were preincubated with various chemokines or GF, and then allowed to migrate toward medium containing 10% FBS, those preincubated with TNF-α showed the highest migratory activity. Next, hAdMSCs were either preincubated or not with TNF-α, and allowed to migrate in response to various GFs or chemokines. Prestimulation with TNF-α increased the migration activity of hAdMSCs compared to unstimulated hAdMSCs. When analyzed by FACS and RT-PCR methods, hAdMSCs were found to express C-C chemokine receptor type 1 (CCR1), CCR7, C-X-C chemokine receptor type 4 (CXCR4), CXCR5, CXCR6, EGF receptor, fibroblast growth factor receptor 1, TGF-β receptor 2, TNF receptor superfamily member 1A, PDGF receptor A and PDGF receptor B at both the protein and the mRNA levels. These results indicate that the migration capacity of hAdMSCs is controlled by various GFs and chemokines. Prior in vitro modulation of the homing capacity of hAdMSCs could stimulate their movement into injured sites in vivo when administered intravenously, thereby improving their therapeutic potential.




Pain Physician. 2008 May-Jun;11(3):343-53.

Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells.

Source

Regenerative Sciences Inc (RSI), Centeno-Schultz Clinic, Westminster, CO 80020, USA.

Abstract

BACKGROUND:

The ability to repair tissue via percutaneous means may allow interventional pain physicians to manage a wide variety of diseases including peripheral joint injuries and osteoarthritis. This review will highlight the developments in cellular medicine that may soon permit interventional pain management physicians to treat a much wider variety of clinical conditions and highlight an interventional case study using these technologies

OBJECTIVE:

To determine if isolated and expanded human autologous mesenchymal stem cells could effectively regenerate cartilage and meniscal tissue when percutaneously injected into knees.

DESIGN:

Case Study

SETTING:

Private Interventional Pain Management practice.

METHODS:

An IRB approved study with a consenting volunteer in which mesenchymal stem cells were isolated and cultured ex-vivo from bone marrow aspiration of the iliac crest. The mesenchymal stem cells were then percutaneously injected into the subject's knee with MRI proven degenerative joint disease. Pre- and post-treatment subjective visual analog pain scores, physical therapy assessments, and MRIs measured clinical and radiographic changes.

RESULTS:

At 24 weeks post-injection, the patient had statistically significant cartilage and meniscus growth on MRI, as well as increased range of motion and decreased modified VAS pain scores.

CONCLUSION:

The described process of autologous mesenchymal stem cell culture and percutaneous injection into a knee with symptomatic and radiographic degenerative joint disease resulted in significant cartilage growth, decreased pain and increased joint mobility in this patient. This has significant future implications for minimally invasive treatment of osteoarthritis and meniscal injury.




J Med Case Rep. 2011 Jul 7;5:296.

Regeneration of human bones in hip osteonecrosis and human cartilage in knee osteoarthritis with autologous adipose-tissue-derived stem cells: a case series.

Source

Miplant Stems Clinic, 32-3 Chungdam-Dong, Gangnam-Gu, Fourth Floor, Seoul, Korea. jaewoopak@paksmedical.com.

Abstract

ABSTRACT:

INTRODUCTION:

This is a series of clinical case reports demonstrating that a combination of percutaneously injected autologous adipose-tissue-derived stem cells, hyaluronic acid, platelet rich plasma and calcium chloride may be able to regenerate bones in human osteonecrosis, and with addition of a very low dose of dexamethasone, cartilage in human knee osteoarthritis.

CASE REPORTS:

Stem cells were obtained from adipose tissue of abdominal origin by digesting lipoaspirate tissue with collagenase. These stem cells, along with hyaluronic acid, platelet rich plasma and calcium chloride, were injected into the right hip of a 29-year-old Korean woman and a 47-year-old Korean man. They both had a history of right hip osteonecrosis of the femoral head. For cartilage regeneration, a 70-year-old Korean woman and a 79-year-old Korean woman, both with a long history of knee pain due to osteoarthritis, were injected with stem cells along with hyaluronic acid, platelet rich plasma, calcium chloride and a nanogram dose of dexamethasone. Pre-treatment and post-treatment MRI scans, physical therapy, and pain score data were then analyzed.

CONCLUSIONS:

The MRI data for all the patients in this series showed significant positive changes. Probable bone formation was clear in the patients with osteonecrosis, and cartilage regeneration in the patients with osteoarthritis. Along with MRI evidence, the measured physical therapy outcomes, subjective pain, and functional status all improved. Autologous mesenchymal stem cell injection, in conjunction with hyaluronic acid, platelet rich plasma and calcium chloride, is a promising minimally invasive therapy for osteonecrosis of femoral head and, with low-dose dexamethasone, for osteoarthritis of human knees.





Med Hypotheses. 2008 Dec;71(6):900-8. Epub 2008 Sep 10.

Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells.

Source

Regenerative Sciences Inc, Centeno-Schultz Clinic, Westminster, CO 80020, USA.

Abstract

Mesenchymal stem cells are pluripotent cells found in multiple human tissues including bone marrow, synovial tissues, and adipose tissues. They have been shown to differentiate into bone, cartilage, muscle, and adipose tissue and represent a possible promising new therapy in regenerative medicine. Because of their multi-potent capabilities, mesenchymal stem cell (MSC) lineages have been used successfully in animal models to regenerate articular cartilage and in human models to regenerate bone. The regeneration of articular cartilage via percutaneous introduction of mesenchymal stem cells (MSC's) is a topic of significant scientific and therapeutic interest. Current treatment for cartilage damage in osteoarthritis focuses on surgical interventions such as arthroscopic debridement, microfracture, and cartilage grafting/transplant. These procedures have proven to be less effective than hoped, are invasive, and often entail a prolonged recovery time. We hypothesize that autologous mesenchymal stem cells can be harvested from the iliac crest, expanded using the patient's own growth factors from platelet lysate, then successfully implanted to increase cartilage volume in an adult human knee. We present a review highlighting the developments in cellular and regenerative medicine in the arena mesenchymal stem cell therapy, as well as a case of successful harvest, expansion, and transplant of autologous mesenchymal stem cells into an adult human knee that resulted in an increase in meniscal cartilage volume.




BMC Musculoskelet Disord. 2011 Nov 15;12:259.

Homing and reparative effect of intra-articular injection of autologous mesenchymal stem cells in osteoarthritic animal model.

Source

Department of rheumatology and rehabilitation, Faculty of Medicine, Cairo University, Egypt.

Abstract

BACKGROUND:

This work aimed to study the homing evidence and the reparative effect of mesenchymal stem cells (MSCs) in the healing process of induced osteoarthritis in experimental animal model (donkeys).

METHODS:

Twenty-seven donkeys were equally divided into 3 groups based on the observation period after induction of arthritis (3, 6 and 9 weeks) to achieve different degrees of osteoarthritis. Each group was subdivided into three subgroups of three animals each based on the follow-up period (1, 2 and 6 months) after treatment. The induction was done through intra-articular (IA) injection of 2 ml of Amphotericin-B in both carpal joints. MSCs were harvested in a separate procedure, labeled with green fluorescent protein (GFP) using monster GFP vector and suspended in hyaluronic acid for IA injection. Treatment approaches consisted of cell-treatment using MSCs suspended in 3 ml of hyaluronic acid (HA) for the right carpal joint; and using the same amount of (HA) but without MSCs for the left contralateral carpal joint to serve as a control. Animals were assessed clinically and radiologically before and after treatment. Synovial fluid was also evaluated. Histopathologically; articular cartilage structural changes, reduction of articular cartilage matrix staining, osteophyte formation, and subchondral bone plate thickening were graded. Data was summarized using median and percentile for scores of histopathologic grading. Comparison between groups was done using non-parametric Mann Whitney test.

RESULTS:

The reparative effect of MSCs was significant both clinically and radiologically in all treated groups (P < 0.05) compared to the control groups. Fluorescence microscopy of sections of the cell-treated joints of all animals indicated that the GFP-transduced injected cells have participated effectively in the reparative process of the damaged articular surface and have integrated within the existing articular cartilage. The cells were associated with the surface of the cartilage and, were also detected in the interior.

CONCLUSIONS:

Homing was confirmed by the incorporation of injected GFP-labeled MSCs within the repaired newly formed cartilage. Significant recovery proves that the use of IA injection of autologous MSCs is a viable and a practical option for treating different degrees of osteoarthritis.




Stem Cell Res Ther. 2011 Mar 18;2(2):14.

Mesenchymal stem cell-based therapies in regenerative medicine: applications in rheumatology.

Source

Inserm, U844, Montpellier, F-34091 France. daniele.noel@inserm.fr.

Abstract

Growing knowledge on the biology of mesenchymal stem cells (MSCs) has provided new insights into their potential clinical applications, particularly for rheumatologic disorders. Historically, their potential to differentiate into cells of the bone and cartilage lineages has led to a variety of experimental strategies to investigate whether MSCs can be used for tissue engineering approaches. Beyond this potential, MSCs also display immunosuppressive properties, which have prompted research on their capacity to suppress local inflammation and tissue damage in a variety of inflammatory autoimmune diseases and, in particular, in rheumatoid arthritis. Currently, an emerging field of research comes from the possibility that these cells, through their trophic/regenerative potential, may also influence the course of chronic degenerative disorders and prevent cartilage degradation in osteoarthritis. This review focuses on these advances, specifically on the biological properties of MSCs, including their immunoregulatory characteristics, differentiation capacity and trophic potential, as well as the relevance of MSC-based therapies for rheumatic diseases.


Clin Immunol. 2011 Dec;141(3):328-37. Epub 2011 Sep 2.

Administering human adipose-derived mesenchymal stem cells to prevent and treat experimental arthritis.

Source

Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA.

Abstract

Rheumatoid arthritis is a chronic autoimmune disease and affecting approximately 1% of the population. Human adipose-derived mesenchymal stem cells (hASCs) were recently found to suppress effector T cell and inflammatory responses and, thus, to have beneficial effects in various autoimmune diseases. In this study, we examined whether hASCs could play a protective and/or therapeutic role in collagen-induced arthritis (CIA). We showed that hASCs both prevented and treated CIA by significantly reducing the incidence and severity of experimental arthritis. We further demonstrated that treatment with hASCs inhibited the production of various inflammatory mediators, decreased antigen-specific Th1/Th17 cell expansion, and induced the production of anti-inflammatory cytokine interleukin-10. Moreover, hASCs could induce the generation of antigen-specific Treg cells with the capacity to suppress collagen-specific T cell responses.


Myocardial regeneration potential of adipose tissue-derived stem cells.

Bai X, Alt E.

Source Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe, Houston, TX 77030, USA.

Abstract

Various tissue resident stem cells are receiving attention from basic scientists and clinicians as they hold promise for myocardial regeneration. For practical reasons, adipose tissue-derived stem cells (ASCs) are attractive cells for clinical application in repairing damaged myocardium based on the following advantages: abundant adipose tissue in most patients and easy accessibility with minimally invasive lipoaspiration procedure. Several recent studies have demonstrated that both cultured and freshly isolated ASCs could improve cardiac function in animal model of myocardial infarction. The mechanisms underlying the beneficial effect of ASCs on myocardial regeneration are not fully understood. Growing evidence indicates that transplantation of ASCs improve cardiac function via the differentiation into cardiomyocytes and vascular cells, and through paracrine pathways. Paracrine factors secreted by injected ASCs enhance angiogenesis, reduce cell apoptosis rates, and promote neuron sprouts in damaged myocardium. In addition, Injection of ASCs increases electrical stability of the injured heart. Furthermore, there are no reported cases of arrhythmia or tumorigenesis in any studies regarding myocardial regeneration with ASCs. This review summarizes the characteristics of both cultured and freshly isolated stem cells obtained from adipose tissue, their myocardial regeneration potential, and the underlying mechanisms for beneficial effect on cardiac function, and safety issues.


Arterioscler Thromb Vasc Biol. 2009 Jan;29(1):61-6. Epub 2008 Oct 30.

Implantation of adipose-derived regenerative cells enhances ischemia-induced angiogenesis.

Kondo K, Shintani S, Shibata R, Murakami H, Murakami R, Imaizumi M, Kitagawa Y, Murohara T.

Source Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, 466-8550 Japan.

 

 

Abstract

Therapeutic angiogenesis using autologous stem/progenitor cells represents a novel strategy for severe ischemic diseases. Recent reports indicated that adipose tissues could supply adipose-derived regenerative cells (ADRCs). Accordingly, we examined whether implantation of ADRCs would augment ischemia-induced angiogenesis.

 

CONCLUSIONS: Adipose tissue would be a valuable source for cell-based therapeutic angiogenesis. Moreover, chemokine SDF-1 may play a pivotal role in the ADRCs-mediated angiogenesis at least in part by facilitating mobilization of EPCs.


A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction.

Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, Gerstenblith G, DeMaria AN, Denktas AE, Gammon RS, Hermiller JB Jr, Reisman MA, Schaer GL, Sherman W.

Source Department of Medicine, Cardiovascular Division and the Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA. jhare@med.miami.edu

Abstract

OBJECTIVES: Our aim was to investigate the safety and efficacy of intravenous allogeneic human mesenchymal stem cells (hMSCs) in patients with myocardial infarction (MI).

BACKGROUND: Bone marrow-derived hMSCs may ameliorate consequences of MI, and have the advantages of preparation ease, allogeneic use due to immunoprivilege, capacity to home to injured tissue, and extensive pre-clinical support.

METHODS: We performed a double-blind, placebo-controlled, dose-ranging (0.5, 1.6, and 5 million cells/kg) safety trial of intravenous allogeneic hMSCs (Prochymal, Osiris Therapeutics, Inc., Baltimore, Maryland) in reperfused MI patients (n=53). The primary end point was incidence of treatment-emergent adverse events within 6 months. Ejection fraction and left ventricular volumes determined by echocardiography and magnetic resonance imaging were exploratory efficacy end points.

RESULTS: Adverse event rates were similar between the hMSC-treated (5.3 per patient) and placebo-treated (7.0 per patient) groups, and renal, hepatic, and hematologic laboratory indexes were not different. Ambulatory electrocardiogram monitoring demonstrated reduced ventricular tachycardia episodes (p=0.025), and pulmonary function testing demonstrated improved forced expiratory volume in 1 s (p=0.003) in the hMSC-treated patients. Global symptom score in all patients (p=0.027) and ejection fraction in the important subset of anterior MI patients were both significantly better in hMSCs versus placebo subjects. In the cardiac magnetic resonance imaging substudy, hMSC treatment, but not placebo, increased left ventricular ejection fraction and led to reverse remodeling.

CONCLUSIONS: Intravenous allogeneic hMSCs are safe in patients after acute MI. This trial provides pivotal safety and provisional efficacy data for an allogeneic bone marrow-derived stem cell in post-infarction patients. (Safety Study of Adult Mesenchymal Stem Cells [MSC] to Treat Acute Myocardial Infarction; NCT00114452).

 


World J Gastroenterol. 2008 Aug 7;14(29):4616-26.

Inflammatory bowel disease: Moving toward a stem cell-based therapy.

Source

Department of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, Bologna, Italy.

Abstract

The incidence and prevalence of Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel diseases (IBD), are rising in western countries. The modern hygienic lifestyle is probably at the root of a disease where, in genetically susceptible hosts, the intestinal commensal flora triggers dysregulated immune and inflammatory responses. Current therapies ranging from anti-inflammatory drugs to immunosuppressive regimens, remain inadequate. Advances in our understanding of the cell populations involved in the pathogenetic processes and recent findings on the regenerative, trophic and immunoregulatory potential of stem cells open new paths in IBD therapy. Hematopoietic and mesenchymal stem cells are catalyzing the attention of IBD investigators. This review highlights the pivotal findings for stem cell-based approaches to IBD therapy and collects the encouraging results coming in from clinical trials.


Dis Colon Rectum. 2005 Jul;48(7):1416-23.

A phase I clinical trial of the treatment of Crohn's fistula by adipose mesenchymal stem cell transplantation.

Source

Department of General Surgery, La Paz University Hospital, Madrid, Spain. damian.garcia@uam.es

Abstract

PURPOSE:

The effective management of fistulas in patients with Crohn's disease presents an extremely challenging problem. Mesenchymal adult stem cells extracted from certain tissues, such as adipose tissue, can differentiate into various cell types. Therefore, we have tried to use such cells to stimulate healing of Crohn's fistulas.

METHODS:

We designed a prospective Phase I clinical trial, involving five patients with Crohn's disease, to test the feasibility and safety of autologous stem cells transplantation in the treatment of fistulas. We also studied the expression of various cell markers and the growth rates of the lipoaspirate-derived cells that were used for transplantation.

RESULTS:

One patient was excluded because of bacterial contamination of cultured cells. We inoculated nine fistulas in four patients with autologous adipose tissue-derived stem cells at Passage 3 or earlier. Eight inoculated fistulas were followed weekly for at least eight weeks. In six fistulas, the external opening was covered with epithelium at the end of Week 8, and, thus, these fistulas were considered healed (75 percent). In the other two fistulas, there was only incomplete closure of the external opening, with a decrease in output flow (not healed; 25 percent). No adverse effects were observed in any patient at the end of the follow-up period (minimum follow-up,12 months; maximum follow-up, 30 months; follow-up average, 22 months).

CONCLUSIONS:

To our knowledge, this is the first report of a clinical trial of cell therapy using autologous stem cells obtained from a lipoaspirate. Our results indicate that our protocol is feasible and safe for the treatment of fistulas in Crohn's disease. The number of patients included and the uncontrolled nature of Phase I clinical trials do not allow demonstration of the effectiveness of the treatment. However, the results of the present study encourage to perform further studies in Phase II.


Dis Colon Rectum. 2009 Jan;52(1):79-86.

Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial.

Source

Department of Surgery and Cell Therapy, La Paz University Hospital, Universidad Autónoma de Madrid, Madrid, Spain. damian.garcia@uam.es

Abstract

PURPOSE:

The feasibility and safety of stem cell-based therapy with expanded adipose-derived stem cells (ASCs) has been investigated in a phase I clinical trial. The present study was designed as a phase II multicenter, randomized controlled trial to further investigate the effectiveness and safety of ASCs in the treatment of complex perianal fistulas.

METHODS:

Patients with complex perianal fistulas (cryptoglandular origin, n = 35; associated with Crohn's disease, n = 14) were randomly assigned to intralesional treatment with fibrin glue or fibrin glue plus 20 million ASCs. Fistula healing and quality of life (SF-12 questionnaire) were evaluated at eight weeks and one year. If healing was not seen at eight weeks, a second dose of fibrin glue or fibrin glue plus 40 million ASCs was administered.

RESULTS:

Fistula healing was observed in 17 (71 percent) of 24 patients who received ASCs in addition to fibrin glue compared with 4 (16 percent) of 25 patients who received fibrin glue alone (relative risk for healing, 4.43; confidence interval, 1.74-11.27); P < 0.001). The proportion of patients with healing was similar in Crohn's and non-Crohn's subgroups. ASCs were also more effective than fibrin glue alone in patients with a suprasphincteric fistulous tract (P = 0.001). Quality of life scores were higher in patients who received ASCs than in those who received fibrin glue alone. At one year follow-up, the recurrence rate in patients treated with ASCs was 17.6 percent. Both treatments were well tolerated.

CONCLUSION:

Administration of expanded ASCs (20 to 60 million cells) in combination with fibrin glue is an effective and safe treatment for complex perianal fistula and appears to achieve higher rates of healing than fibrin glue alone.


 

J Transl Med. 2011 Oct 21;9:181.

Stem cell treatment for patients with autoimmune disease by systemic infusion of culture-expanded autologous adipose tissue derived mesenchymal stem cells.

Source

Stem Cell Research Center, RNL BIO, Seoul, 153-768, Republic of Korea. jcra@rnl.co.kr

Abstract

Prolonged life expectancy, life style and environmental changes have caused a changing disease pattern in developed countries towards an increase of degenerative and autoimmune diseases. Stem cells have become a promising tool for their treatment by promoting tissue repair and protection from immune-attack associated damage. Patient-derived autologous stem cells present a safe option for this treatment since these will not induce immune rejection and thus multiple treatments are possible without any risk for allogenic sensitization, which may arise from allogenic stem cell transplantations. Here we report the outcome of treatments with culture expanded human adipose-derived mesenchymal stem cells (hAdMSCs) of 10 patients with autoimmune associated tissue damage and exhausted therapeutic options, including autoimmune hearing loss, multiple sclerosis, polymyotitis, atopic dermatitis and rheumatoid arthritis. For treatment, we developed a standardized culture-expansion protocol for hAdMSCs from minimal amounts of fat tissue, providing sufficient number of cells for repetitive injections. High expansion efficiencies were routinely achieved from autoimmune patients and from elderly donors without measurable loss in safety profile, genetic stability, vitality and differentiation potency, migration and homing characteristics. Although the conclusions that can be drawn from the compassionate use treatments in terms of therapeutic efficacy are only preliminary, the data provide convincing evidence for safety and therapeutic properties of systemically administered AdMSC in human patients with no other treatment options. The authors believe that ex-vivo-expanded autologous AdMSCs provide a promising alternative for treating autoimmune diseases. Further clinical studies are needed that take into account the results obtained from case studies as those presented here.


Pathology. 2011 Oct;43(6):592-604.

Potential therapeutic applications of mesenchymal stromal cells.

Source

Institute of Haematology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.

Abstract

Mesenchymal stromal cells (MSCs) are a non-homogeneous population of plastic-adherent cells which were initially isolated from post-natal bone marrow. They have the capacity to differentiate to multiple mesodermal lineages including bone, cartilage and adipose tissue. In stringent culture conditions, MSCs can also be induced to differentiate into different cell types of endoderm and neuroectoderm lineages. To date, no specific marker identifies MSCs, although a number of cell surface antigens have been described which enrich for MSCs. Mesenchymal stromal cells possess a number of properties which have generated considerable interest in diverse cellular therapeutic applications. The capacity of MSCs to differentiate into multiple different cell lineages has seen them actively explored for tissue repair, particularly in cardiac, orthopaedic and neurological applications. A large body of data indicates that MSCs possess immunomodulatory properties. Mesenchymal stromal cells are immunosuppressive, interacting with T lymphocytes, antigen presenting cells, B lymphocytes, and natural killer cells. In addition, they are immunoprivileged, allowing transplantation across allogeneic barriers. These immunomodulatory properties have seen infusion of MSCs for the treatment of steroid refractory graft versus host disease, a life threatening complication of haemopoietic cell transplantation, with promising results. Furthermore, these immune functions may lead to roles in the facilitation of engraftment, induction of tolerance and as therapy in autoimmune disease.


Stem Cells. 2009 Jun;27(6):1421-32.

Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans.

Source

Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.

Abstract

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that, despite the advances in immunosuppressive medical therapies, remains potentially fatal in some patients, especially in treatment-refractory patients. Here, we reported that impairment of bone marrow mesenchymal stem cells (BMMSCs) and their associated osteoblastic niche deficiency contribute in part to the pathogenesis of SLE-like disease in MRL/lpr mice. Interestingly, allogenic BMMSC transplantation (MSCT) is capable of reconstructing the bone marrow osteoblastic niche and more effectively reverses multiorgan dysfunction when compared with medical immunosuppression with cyclophosphamide (CTX). At the cellular level, MSCT, not CTX treatment, was capable to induce osteoblastic niche reconstruction, possibly contributing to the recovery of regulatory T-cells and reestablishment of the immune homeostasis. On the basis of the promising clinical outcomes in SLE mice, we treated four CTX/glucocorticoid treatment-refractory SLE patients using allogenic MSCT and showed a stable 12-18 months disease remission in all treated patients. The patients benefited an amelioration of disease activity, improvement in serologic markers and renal function. These early evidences suggest that allogenic MSCT may be a feasible and safe salvage therapy in refractory SLE patients.

 

 

Ann Rheum Dis. 2010 Aug;69(8):1423-9.

Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study.

Liang J, Zhang H, Hua B, Wang H, Lu L, Shi S, Hou Y, Zeng X, Gilkeson GS, Sun L.

Source

Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School , Nanjing, China .

Abstract

OBJECTIVE:

To determine the safety and efficacy of allogeneic mesenchymal stem cell transplantation (MSCT) in refractory systemic lupus erythematosus (SLE).

METHODS:

A total of 15 patients with persistently active SLE underwent MSCT. Outcome was evaluated by changes in the SLE disease activity index (SLEDAI), serological features (anti-nuclear antibodies and anti-double-stranded DNA (anti-dsDNA)), renal function and percentage of peripheral blood regulatory T cells.

RESULTS:

From 11 March 2007 to 4 November 2008, 15 patients with persistently active SLE were enrolled and underwent MSCT. The mean follow-up period was 17.2+/-9.5 months. A total of 13 patients have been followed for more than 12 months. All patients clinically improved following treatment with mesenchymal stem cells with a marked decrease in the SLEDAI score and 24 h proteinuria. At 12-month follow-up, SLEDAI scores decreased from 12.2+/-3.3 to 3.2+/-2.8 and proteinuria decreased from 2505.0+/-1323.9 to 858.0+/-800.7 mg/24 h (all p<0.05, by paired t test, n=12). At 1-year follow-up in 13 patients, 2 had a relapse of proteinuria, while the other 11 continue to have decreased disease activity on minimal treatment. Anti-dsDNA levels decreased. Improvement in glomerular filtration rate was noted in two patients in which formal testing was performed. Non-renal-related manifestations also improved significantly. No serious adverse events were reported.

CONCLUSION:

Allogeneic MSCT in patients with refractory lupus resulted in amelioration of disease activity, improvement in serological markers and stabilisation of renal function. MSCT appears beneficial in treatment of patients with SLE refractory to conventional treatment options.

 

 

Hematopoietic Stem Cell Transplantation for Systemic Lupus Erythematosus

 

Alberto M. Marmont du Haut Champ*

 

 

Division of Hematology and Stem Cell Transplantation, IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genoa, Italy

 

 

*Alberto M. Marmont du Haut Champ: alberto.marmont@hsanmartino.it

 

 

Academic Editor: Roberto Caricchio

 

 

Author information ► Article notes ► Copyright and License information ►

 

 

Received March 9, 2012; Revised June 6, 2012; Accepted July 3, 2012.

 

 

Copyright © 2012 Alberto M. Marmont du Haut Champ.

 

 

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

 

 

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Abstract

 

Two streams of research are at the origin of the utilization of hematopoietic stem cell transplantation (HSCT) for severe autoimmune diseases (SADs). The allogeneic approach came from experimental studies on lupus mice, besides clinical results in coincidental diseases. The autologous procedure was encouraged by researches on experimental neurological and rheumatic disorders. At present the number of allogeneic HSCT performed for human SADs can be estimated to not over 100 patients, and the results are not greatly encouraging, considering the significant transplant-related mortality (TRM) and the occasional development of a new autoimmune disorder and/or relapses notwithstanding full donor chimerism. Autologous HSCT for refractory SLE has become a major target. Severe cases have been salvaged, TRM is low and diminishing, and prolonged clinical remissions are obtainable. Two types of immune resetting have been established, “re-education” and regulatory T cell (Tregs) normalization. Allogeneic HSCT for SLE seems best indicated for patients with disease complicated by an oncohematologic malignancy. Autologous HSCT is a powerful salvage therapy for otherwise intractable SLE. The duration of remission in uncertain, but a favorable response to previously inactive treatments is a generally constant feature. The comparison with new biological agents, or the combination of both, are to be ascertained.

 

Autologous Transplantation

 

 

Hematopoietic stem cell transplantation (HSCT), especially in its autologous form, has become a significant treatment modality for severe autoimmune diseases [19] (SADs), and more specifically for systemic lupus erythematosus (SLE) and the antiphospholipid syndrome [1014]. Most of the evidence concerns the hematopoietic lineage. However, the utilization of another distinct lineage, consisting of mesenchymal stromal cells (MSC), is also becoming a promising sector in the field of regenerative medicine and immune disorders [15, 16]. Bone mesenchymal stem cells (BMSC) are not transplanted along with hematopoiesis in standard marrow and blood transplantation [17]. However there are 2 important studies in which allogeneic MSC were transplanted in patients with severe-refractory SLE. In both, no pretransplant conditioning was utilized because of the well-known low MSC immunogenicity. Fifteen lupus patients received 1 intravenous infusion of 1 × 106 MSC/Kg, and both the clinical (by SLEDAI score) and the laboratory (DNA, ANA) results were clearly favorable [18]. Another study by the same investigators was performed with umbilical MSC, utilizing low-dose cyclophosphamide (CY) conditioning in about half of them, in 16 lupus patients, again with significant amelioration in SLEDAI and laboratory results [19], which were accompanied by an increase in peripheral Treg cells, a feature that was also found in other SLE patients treated with conventional autologous HSCT [20].

The first two reports of patients with severe, refractory SLE having undergone auto-HSCT were published in 1997 [64, 65]. The patient transplanted in Genoa had a long history of lupus with many severe complications, and has been followed to the time of this writing, making it the longest followup of a single patient (16 years; see Table 1). There followed a series of single case reports, all of them characterized by an extremely severe condition associated with complete refractoriness to conventional therapy. They included patients with refractory SLE in general [66], with severe pulmonary involvement [67], and with complicating Evans' syndrome [68]. Of special interest are two cases of neuropsychiatric SLE (NP-SLE) that were salvaged by auto-HSCT [69, 70]. These case reports paved the way to single center retrospective clinical studies, and subsequently to more extended cooperative ones. They are not to be disregarded, since patients in desperate conditions were rescued by means of the bold and knowledgeable utilization of a procedure until then mostly ignored in this specific area. Single-case reports are known to be classified at the lowest degree of strength in observational studies, but they are considered of interest when reporting “newly recognized or uncommon observations” [71], and this is the case of these pioneering interventions. More extensive clinical trials by dedicated teams were to follow worldwide. They have been resumed in 2 tables, one in the recent summation by Illei et al. [13] and another published in a former contribution by us [72]. Two fundamental findings emerged from these clinical observations, namely the powerful therapeutic effect reported by all centers, and the greatly inferior transplant-related mortality (TRM) as compared to the allogeneic procedure.


 Mult Scler. 2009 May;15(5):644-6.

Allogeneic mesenchymal stem cells transplantation in treatment of multiple sclerosis.

Source

Department of Immunology and Rheumatology, Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, P. R. China.

Abstract

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system. Umbilical cord derived mesenchymal stem cells are immunosuppressive. We transplanted mesenchymal stem cells in a patient with refractory progressive MS, and the disease course was stabilized after the transplantation. We postulate that mesenchymal stem cells have a potent immunosuppressive effect in vivo.


Curr Stem Cell Res Ther. 2012 May 1;7(3):179-90.

Mesenchymal stem cell-based therapy for the treatment of type 1 diabetes mellitus.

Source

Dr. Soliman Fakeeh Hospital, Hematology Unit, P.O. Box 2537, Jeddah 21461, Kingdome of Saudi Arabia. mohmabed@mans.edu.eg.

Abstract

The pathophysiology of Type 1 diabetes (T1D) appears largely related to an innate defect in the immune system culminating in a loss of self tolerance and destruction of the insulin producing β-cells. Currently, there is no definitive cure for diabetes. Insulin injection does not mimic the precise regulation of β-cells on glucose homeostasis, leading long term to the development of complications. Other therapeutic approaches therefore, are necessary and cell therapy is thought to be a possible approach. In this sense, mesenchymal stem cells (MSCs) can offer a promising possibility that deserves to be explored. MSCs are multipotent non-hematopoietic progenitor cells. Their therapeutic potentials have recently been brought into the spotlights of many fields of research. Although the regenerative capabilities of MSCs have been a driving force to initiate studies testing their therapeutic effectiveness, their immunomodulatory properties have been equally exciting. MSCs possess specific immunomodulatory properties that would appear capable of disabling immune dysregulation that leads to β-cell destruction in T1D. Furthermore, MSCs can be sequentially cultured in specially defined conditions and their differentiation extends toward the β-cell phenotype and the formation of insulin producing cells (IPCs). To date, the role of MSCs in T1D remains completely unexplored. We herein summarize multiple strategies that have been proposed and tested for its potential therapeutic benefit for T1D.

 


 

2013 Apr 9. [Epub ahead of print]

Stem Cell Therapy to Cure Type 1 Diabetes: From Hype to Hope.

Source

Department of Surgery, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

Abstract

Type 1 diabetes mellitus (T1D) is a chronic, multifactorial autoimmune disease that involves the progressive destruction of pancreatic β-cells, ultimately resulting in the loss of insulin production and secretion. The goal of clinical intervention is to prevent or arrest the onset and progression of autoimmunity, reverse β-cell destruction, and restore glycometabolic and immune homeostasis. Despite promising outcomes observed with islet transplantation and advancements in immunomodulatory therapies, the need for an effective cell replacement strategy for curing T1D still persists. Stem cell therapy offers a solution to the cited challenges of islet transplantation. While the regenerative potential of stem cells can be harnessed to make available a self-replenishing supply of glucose-responsive insulin-producing cells, their immunomodulatory properties may potentially be used to prevent, arrest, or reverse autoimmunity, ameliorate innate/alloimmune graft rejection, and prevent recurrence of the disease. Herein, we discuss the therapeutic potential of stem cells derived from a variety of sources for the cure of T1D, for example, embryonic stem cells, induced pluripotent stem cells, bone marrow-derived hematopoietic stem cells, and multipotent mesenchymal stromal cells derived from bone marrow, umbilical cord blood, and adipose tissue. The benefits of combinatorial approaches designed to ensure the successful clinical translation of stem cell therapeutic strategies, such as approaches combining effective stem cell strategies with islet transplantation, immunomodulatory drug regimens, and/or novel bioengineering techniques, are also discussed. To conclude, the application of stem cell therapy in the cure for T1D appears extremely promising


Regen Med. 2011 Sep;6(5):599-605.

The therapeutic role of endothelial progenitor cells in Type 1 diabetes mellitus.

Source

Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.

Abstract

Pancreatic β-cells sense and adjust the blood glucose level by secretion of insulin. In Type 1 diabetes mellitus, these insulin-producing cells are destroyed, leaving the patients incapable of regulating blood glucose homeostasis. At the time of diagnosis, most patients still have 20-30% of their original β-cell mass remaining. These residual β-cells are targets for intervention therapies aimed at preventing further autoimmune destruction, in addition to increasing the number of existing β-cells. Such a therapeutic option is highly desirable since it may lead to a full recovery of newly diagnosed patients, with no need for further treatment with immunosuppressant drugs or exogenous insulin administration. In this article, we propose that endothelial progenitor cells, a cell type known to promote and support neovascularization following endothelial injury, may be used as part of a combinational stem cell therapy aimed to improve the vascularization, survival and proliferation of β-cells.


Diabetes Metab. 2009 Apr;35(2):85-93. Epub 2009 Feb 20.

Mesenchymal stem cells: Stem cell therapy perspectives for type 1 diabetes.

Source

Inserm U697, Paris, France.

Abstract

Mesenchymal stem cells (MSCs) are multipotent non-haematopoietic progenitor cells that are being explored as a promising new treatment for tissue regeneration. Although their immunomodulatory properties are not yet completely understood, their low immunogenic potential together with their effects on immune response make them a promising therapeutic tool for severe refractory autoimmune diseases. Type 1 diabetes is characterized by T cell-mediated autoimmune destruction of pancreatic beta cells. While insulin replacement represents the current therapy for type 1 diabetes, its metabolic control remains difficult, as exogenous insulin cannot exactly mimic the physiology of insulin secretion. Pancreatic or islet transplantation can provide exogenous insulin independence, but is limited by its intrinsic complications and the scarcity of organ donors. In this context, stem cell therapy, based on the generation of insulin-producing cells (IPCs) derived from MSCs, represents an attractive possibility. In this review, we provide a brief characterization of MSC immunomodulatory effects, and present the current experimental evidence for the potential therapeutic efficacy of MSC transplantation in diabetes.


Med Hypotheses. 2008 Sep;71(3):390-3. Epub 2008 Jun 6.

Mesenchymal stem cell therapy for diabetes through paracrine mechanisms.

Source

Department of Endocrinology, Qilu Hospital, Shandong University, Jinan, PR China.

Abstract

Type 1 diabetes is a chronic disorder characterized by the destruction of pancreatic islet beta-cells through autoimmune assault. Insulin replacement is the current main therapeutic approach. In recent years, several studies have showed that mesenchymal stem cells (MSCs) transplantation can improve the metabolic profiles of diabetic animal models. However the exact mechanisms of reversing hyperglycemia remain to be elusive. Trans-differentiation of MSCs into insulin-producing cells (IPCs) has ever been regarded as the main mechanism. But other reports have contradicted these findings and it is difficult to explain the timing and extent of improvement by only the effect through trans-differentiation. Researches have found that MSCs naturally produce a variety of cytokines and growth factors, promoting the survival of surrounding cells, called as paracrine mechanisms. Paracrine effects have been proved to play an important role in tissue regeneration and repair in recent researches. Therefore we speculate that MSCs transplantation into diabetic animals may prevent apoptosis of injured pancreatic beta cells and enhance regeneration of endogenous progenitor cells through paracrine actions such as angiogenic, cytoprotective, anti-inflammatory, mitogenic and anti-apoptotic effects. This hypothesis, if proved to be valid, may represent an important breakthrough in developing effective molecular or genetic therapeutics for diabetes.

 


Non-expanded adipose stromal vascular fraction cell therapy for multiple sclerosis.

Neil H Riordan,1 Thomas E Ichim, 1 Wei-Ping Min,2 Hao Wang,2 Fabio Solano,3 Fabian Lara,3 Miguel Alfaro,4 Jorge Paz Rodriguez,5 Robert J Harman,6 Amit N Patel,7 Michael P Murphy,8 Roland R Lee,9,10 and Boris Minev11,12

1Medistem Inc, San Diego, CA, USA ;2Department of Surgery, University of Western Ontario, London, Ontario, Canada ;3Cell Medicine Institutes, San Jose, Costa Rica ;4Hospital CIMA, San Jose, Costa Rica ;5Cell Medicine Institutes, Panama City, Panama ;6Vet-Stem, Inc. Poway, CA, USA ; 7Dept of Cardiothoracic Surgery, University of Utah, Salt Lake City, Utah, USA ;8Division of Medicine, Indiana University School of Medicine, Indiana, USA ; 9Department of Radiology, University of Canlfornia San Diego, San Diego, CA, USA ; 10Veterans Administration, San Diego, CA, USA; 11Moores Cancer Center, University of California, San Diego, CA, USA ; 12Department of Medicine, Division of Neurosurgery, University of California San Diego, San Diego, CA, USA ; Corresponding author. Neil H Riordan: riordan@medisteminc.com ; Thomas E Ichim: thomas.ichim@gmail.com ; Wei-Ping Min: weiping.min@uwo.ca ; Hao Wang: hwang1@uwo.ca ; Fabio Solano: doctorsolano@gmail.com ; Fabian Lara: drfabianlara@gmail.com ; Miguel Alfaro: thomas.ichim@mail.com ; Jorge Paz Rodriguez: thomas.ichim@gmail.com ; Robert J Harman: bharman@vet-stem.com ; Amit N Patel: dallaspatel@gmail.com ; Michael P Murphy: mipmurph@iupui.edu ; Roland R Lee: rrlee@ucsd.edu ; Boris Minev: bminev@ucsd.edu ; Received March 16, 2009; Accepted April 24, 2009.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The stromal vascular fraction (SVF) of adipose tissue is known to contain mesenchymal stem cells (MSC), T regulatory cells, endothelial precursor cells, preadipocytes, as well as anti-inflammatory M2 macrophages. Safety of autologous adipose tissue implantation is supported by extensive use of this procedure in cosmetic surgery, as well as by ongoing studies using in vitro expanded adipose derived MSC. Equine and canine studies demonstrating anti-inflammatory and regenerative effects of non-expanded SVF cells have yielded promising results. Although non-expanded SVF cells have been used successfully in accelerating healing of Crohn's fistulas, to our knowledge clinical use of these cells for systemic immune modulation has not been reported. In this communication we discuss the rationale for use of autologous SVF in treatment of multiple sclerosis and describe our experiences with three patients. Based on this rationale and initial experiences, we propose controlled trials of autologous SVF in various inflammatory conditions.


Clin Neurol Neurosurg. 2008 Nov;110(9):889-96. Epub 2008 Mar 28.

The potential use of stem cells in multiple sclerosis: an overview of the preclinical experience.

Karussis D, Kassis I.

Source Department of Neurology, Laboratory of Neuroimmunology, Agnes-Ginges Center for Neurogenetics, Hadassah-Hebrew University Hospital, Ein-Karem, Jerusalem, Israel. karus@cc.huji.ac.il

Abstract

The reported neurodegeneration process in multiple sclerosis may explain the lack of efficacy of the currently used immunomodulating modalities and the irreversible axonal damage, which results in accumulating disability. Efforts for neuroprotective treatments have not been, so far, successful in clinical studies in other CNS diseases. Therefore, for MS, the use of stem cells may provide a logical solution, since these cells can migrate locally into the areas of white matter lesions (plaques) and have the potential to support local neurogenesis and rebuilding of the affected myelin. This may be achieved both by support of the resident CNS stem cells repertoire and by differentiation of the transplanted cells into neurons and myelin-producing cells (oligodendrocytes). Stem cells were also shown to possess immunomodulating properties, inducing systemic and local suppression of the myelin-targeting autoimmune lymphocytes. Several types of stem cells (embryonic and adult) have been described and extensively studied in animal models of CNS diseases. In this review, we summarize the experience with the use of different types of stem cells in the animal models of MS (EAE) and we describe the advantages and disadvantages of each stem cell type for future clinical applications in MS.


Lancet Neurol. 2011 Jul;10(7):649-56. Stem Cell Rev. 2010 Dec;6(4):500-6.

A consensus statement addressing mesenchymal stem cell transplantation for multiple sclerosis: it's time!

Siatskas C, Payne NL, Short MA, Bernard CC.

Source Monash immunology and stem cell laboratories, Monash University, Clayton, Victoria, 3800, Australia. christopher.siatskas@monash.edu

Abstract

Multiple sclerosis is a neurodegenerative disease of the central nervous system that is characterized by inflammation, demyelination with associated accumulation of myelin debris, oligodendrocyte and axonal loss. Current therapeutic interventions for multiple sclerosis predominantly modulate the immune system and reduce the inflammatory insult by general, non-specific mechanisms but have little effect on the neurodegenerative component of the disease. Predictably, the overall long-term impact of treatment is limited since the neurodegenerative component of the disease, which can be the dominant process in some patients, determines permanent disability. Mesenchymal stem cells, which are endowed with potent immune regulatory and neuroprotective properties, have recently emerged as promising cellular vehicles for the treatment of MS. Preclinical evaluation in experimental models of MS have shown that MSCs are efficacious in suppressing clinical disease. Mechanisms that may underlie these effects predominantly involve the secretion of immunomodulatory and neurotrophic growth factors, which collectively act to limit CNS inflammation, stimulate neurogenesis, protect axons and promote remyelination. As a logical progression to clinical utility, the safety of these cells have been initially assessed in hematological, cardiac and inflammatory diseases. Importantly, transplantation with autologous or allogeneic MSCs has been well tolerated by patients with few significant adverse effects. On the basis of these results, new, multicentre clinical trials have been launched to assess the safety and efficacy of MSCs for inflammatory MS. It thus comes as no surprise that the coalescence of an international group of experts have convened to generate a consensus guide for the transplantation of autologous bone marrow-derived MSC which, in time, may set the foundation for the next generation of therapies for the treatment of MS patients.


Arch Neurol. 2010 Oct;67(10):1187-94.

Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis.

Source

Department of Neurology, Hadassah-Hebrew University Hospital, Ein Karem, Jerusalem IL-91120, Israel. karus@cc.huji.ac.il

Abstract

OBJECTIVE:

To evaluate the feasibility, safety, and immunological effects of intrathecal and intravenous administration of autologous mesenchymal stem cells (MSCs) (also called mesenchymal stromal cells) in patients with multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS).

DESIGN:

A phase 1/2 open-safety clinical trial. Patients  Fifteen patients with MS (mean [SD] Expanded Disability Status Scale [EDSS] score, 6.7 [1.0]) and 19 with ALS (mean [SD] Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS] score, 20.8 [8.0]) were enrolled. Intervention  After culture, a mean (SD) of 63.2 × 10(6) (2.5 × 10(6)) MSCs was injected intrathecally (n = 34) and intravenously (n = 14). In 9 cases, MSCs were magnetically labeled with the superparamagnetic iron oxide ferumoxides (Feridex).

MAIN OUTCOME MEASURES:

The main outcome measure was the recording of side effects. Follow-up (≤25 months) included adverse events evaluation, neurological disability assessment by means of the EDSS, magnetic resonance imaging to exclude unexpected pathologies and track the labeled stem cells, and immunological tests to assess the short-term immunomodulatory effects of MSC transplantation.

RESULTS:

Twenty-one patients had injection-related adverse effects consisting of transient fever, and 15 reported headache. No major adverse effects were reported during follow-up. The mean ALSFRS score remained stable during the first 6 months of observation, whereas the mean (SD) EDSS score improved from 6.7 (1.0) to 5.9 (1.6). Magnetic resonance imaging visualized the MSCs in the occipital horns of the ventricles, indicating the possible migration of ferumoxides-labeled cells in the meninges, subarachnoid space, and spinal cord. Immunological analysis revealed an increase in the proportion of CD4(+)CD25(+) regulatory T cells, a decrease in the proliferative responses of lymphocytes, and the expression of CD40(+), CD83(+), CD86(+), and HLA-DR on myeloid dendritic cells at 24 hours after MSC transplantation.

CONCLUSION:

Transplantation of MSCs in patients with MS and ALS is a clinically feasible and relatively safe procedure and induces immediate immunomodulatory effects. Trial Registration  clinicaltrials.gov Identifier: NCT00781872.


Mesenchymal stem cells for the treatment of multiple sclerosis and other neurological diseases.

Uccelli A, Laroni A, Freedman MS.

Source Department of Neurosciences, Ophthalmology, and Genetics, University of Genoa, Italy. auccelli@neurologia.unige.it

Abstract

The rationale for use of adult stem cells as a treatment for neurological diseases such as multiple sclerosis arose from the hope that they had the capacity to foster repair of the CNS through tissue integration and differentiation into neural cells. Evidence from preclinical studies suggested that mesenchymal stem cells (MSCs), a subset of adult progenitor cells, are an effective therapy in preclinical animal models of neurological diseases such as experimental autoimmune encephalomyelitis, a model for multiple sclerosis, and stroke. In experimental autoimmune encephalomyelitis, intravenous injection of MSCs ameliorates clinical course and decreases demyelination, immune infiltrates, and axonal loss. Surprisingly, these effects do not require full CNS engraftment by MSCs, but rely on the capacity of MSCs to inhibit pathogenic immune responses and release neuroprotective and pro-oligodendrogenic molecules favouring tissue repair. These results led to the conclusion that therapeutic use of MSCs should initially focus on individuals with multiple sclerosis and persistent inflammation. Small clinical studies in different neurological diseases have suggested that MSCs are safe, paving the road for larger phase 2 studies addressing the effect of MSCs on clinical outcomes and markers of disease activity 


Zh Nevrol Psikhiatr Im S S Korsakova. 2011;111(2 Pt 2):72-6.

[Transplantation of mesenchymal stem cells in multiple sclerosis].

[Article in Russian]

Abstract

To assess safety and tolerability of treatment with autologic multipotent mesenchymal stem cells (MSC) in multiple sclerosis (MS), we have obtained autologic red bone marrow-derived MSC from 8 patients. Proliferation, immunophenotype and caryotype of MSC, their sterility, the absence of hemopoetic cells, chromosomal aberrations and signs of aging were controlled during the cell growth. The inverse injection of MSC in patient's blood was conducted in accordance to the elaborated protocol in a short intravenous infusion in dose 2.0 x 10(6)/kg of body mass once in 30 days. The duration of treatment was from 4 to 8 months. The efficacy of treatment was assessed after 4, 8 and 12 months. All patients tolerated repeated intravenous infusions of autologic MSC well with no significant side-effects as in the early as well in the remote periods of treatment. The distinct positive effect was seen in some cases 2 months after the beginning of treatment. The improvement of 0.5 point on EDSS was seen in 5/8 patients after 4 months. After 12 months, the improvement of 0.5-1 point on EDSS was seen in 6/8, stabilization in 1/8, progression in 1/8. These results revealed the safety of the elaborated protocol of treatment and the moderate clinical efficacy of treatment in non-curable patients or those with poor response to treatment that suggested continuing the study and enrollment of new patients.


Neurotherapeutics. 2011 Oct;8(4):625-42.

Cell therapy for multiple sclerosis.

Source

Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Hospital, Jerusalem 91120, Israel. tamir@hadassah.org.il

Abstract

The spontaneous recovery observed in the early stages of multiple sclerosis (MS) is substituted with a later progressive course and failure of endogenous processes of repair and remyelination. Although this is the basic rationale for cell therapy, it is not clear yet to what degree the MS brain is amenable for repair and whether cell therapy has an advantage in comparison to other strategies to enhance endogenous remyelination. Central to the promise of stem cell therapy is the therapeutic plasticity, by which neural precursors can replace damaged oligodendrocytes and myelin, and also effectively attenuate the autoimmune process in a local, nonsystemic manner to protect brain cells from further injury, as well as facilitate the intrinsic capacity of the brain for recovery. These fundamental immunomodulatory and neurotrophic properties are shared by stem cells of different sources. By using different routes of delivery, cells may target both affected white matter tracts and the perivascular niche where the trafficking of immune cells occur. It is unclear yet whether the therapeutic properties of transplanted cells are maintained with the duration of time. The application of neural stem cell therapy (derived from fetal brain or from human embryonic stem cells) will be realized once their purification, mass generation, and safety are guaranteed. However, previous clinical experience with bone marrow stromal (mesenchymal) stem cells and the relative easy expansion of autologous cells have opened the way to their experimental application in MS. An initial clinical trial has established the probable safety of their intravenous and intrathecal delivery. Short-term follow-up observed immunomodulatory effects and clinical benefit justifying further clinical trials.


Lancet Neurol. 2012 Feb;11(2):150-6. doi: 10.1016/S1474-4422(11)70305-2. Epub 2012 Jan 10.

Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study.

Source Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Abstract

BACKGROUND:

More than half of patients with multiple sclerosis have progressive disease characterised by accumulating disability. The absence of treatments for progressive multiple sclerosis represents a major unmet clinical need. On the basis of evidence that mesenchymal stem cells have a beneficial effect in acute and chronic animal models of multiple sclerosis, we aimed to assess the safety and efficacy of these cells as a potential neuroprotective treatment for secondary progressive multiple sclerosis.

METHODS:

Patients with secondary progressive multiple sclerosis involving the visual pathways (expanded disability status score 5·5-6·5) were recruited from the East Anglia and north London regions of the UK. Participants received intravenous infusion of autologous bone-marrow-derived mesenchymal stem cells in this open-label study. Our primary objective was to assess feasibility and safety; we compared adverse events from up to 20 months before treatment until up to 10 months after the infusion. As a secondary objective, we chose efficacy outcomes to assess the anterior visual pathway as a model of wider disease. Masked endpoint analyses was used for electrophysiological and selected imaging outcomes. We used piecewise linear mixed models to assess the change in gradients over time at the point of intervention. This trial is registered with ClinicalTrials.gov, number NCT00395200.

FINDINGS:

We isolated, expanded, characterised, and administered mesenchymal stem cells in ten patients. The mean dose was 1·6×10(6) cells per kg bodyweight (range 1·1-2·0). One patient developed a transient rash shortly after treatment; two patients had self-limiting bacterial infections 3-4 weeks after treatment. We did not identify any serious adverse events. We noted improvement after treatment in visual acuity (difference in monthly rates of change -0·02 logMAR units, 95% CI -0·03 to -0·01; p=0·003) and visual evoked response latency (-1·33 ms, -2·44 to -0·21; p=0·020), with an increase in optic nerve area (difference in monthly rates of change 0·13 mm(2), 0·04 to 0·22; p=0·006). We did not identify any significant effects on colour vision, visual fields, macular volume, retinal nerve fibre layer thickness, or optic nerve magnetisation transfer ratio.

INTERPRETATION:

Autologous mesenchymal stem cells were safely given to patients with secondary progressive multiple sclerosis in our study. The evidence of structural, functional, and physiological improvement after treatment in some visual endpoints is suggestive of neuroprotection.


Mult Scler. 2009 May;15(5):644-6.

Allogeneic mesenchymal stem cells transplantation in treatment of multiple sclerosis.

Source

Department of Immunology and Rheumatology, Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, P. R. China.

Abstract

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system. Umbilical cord derived mesenchymal stem cells are immunosuppressive. We transplanted mesenchymal stem cells in a patient with refractory progressive MS, and the disease course was stabilized after the transplantation. We postulate that mesenchymal stem cells have a potent immunosuppressive effect in vivo.


Brain. 2011 Jun;134(Pt 6):1790-807. Epub 2011 Apr 14.

Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke.

Source

Department of Neural Repair and Therapeutics, Sapporo Medical University, South-1st, West-16th, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan. honmou@sapmed.ac.jp

Abstract

Transplantation of human mesenchymal stem cells has been shown to reduce infarct size and improve functional outcome in animal models of stroke. Here, we report a study designed to assess feasibility and safety of transplantation of autologous human mesenchymal stem cells expanded in autologous human serum in stroke patients. We report an unblinded study on 12 patients with ischaemic grey matter, white matter and mixed lesions, in contrast to a prior study on autologous mesenchymal stem cells expanded in foetal calf serum that focused on grey matter lesions. Cells cultured in human serum expanded more rapidly than in foetal calf serum, reducing cell preparation time and risk of transmissible disorders such as bovine spongiform encephalomyelitis. Autologous mesenchymal stem cells were delivered intravenously 36-133 days post-stroke. All patients had magnetic resonance angiography to identify vascular lesions, and magnetic resonance imaging prior to cell infusion and at intervals up to 1 year after. Magnetic resonance perfusion-imaging and 3D-tractography were carried out in some patients. Neurological status was scored using the National Institutes of Health Stroke Scale and modified Rankin scores. We did not observe any central nervous system tumours, abnormal cell growths or neurological deterioration, and there was no evidence for venous thromboembolism, systemic malignancy or systemic infection in any of the patients following stem cell infusion. The median daily rate of National Institutes of Health Stroke Scale change was 0.36 during the first week post-infusion, compared with a median daily rate of change of 0.04 from the first day of testing to immediately before infusion. Daily rates of change in National Institutes of Health Stroke Scale scores during longer post-infusion intervals that more closely matched the interval between initial scoring and cell infusion also showed an increase following cell infusion. Mean lesion volume as assessed by magnetic resonance imaging was reduced by >20% at 1 week post-cell infusion. While we would emphasize that the current study was unblinded, did not assess overall function or relative functional importance of different types of deficits, and does not exclude placebo effects or a contribution of recovery as a result of the natural history of stroke, our observations provide evidence supporting the feasibility and safety of delivery of a relatively large dose of autologous mesenchymal human stem cells, cultured in autologous human serum, into human subjects with stroke and support the need for additional blinded, placebo-controlled studies on autologous mesenchymal human stem cell infusion in stroke.


PLoS One. 2010 Feb 15;5(2):e9200.

Non-invasive stem cell therapy in a rat model for retinal degeneration and vascular pathology.

Wang S, Lu B, Girman S, Duan J, McFarland T, Zhang QS, Grompe M, Adamus G, Appukuttan B, Lund R.

Source

Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States of America. wangsha@ohsu.edu

Abstract

BACKGROUND:

Retinitis pigmentosa (RP) is characterized by progressive night blindness, visual field loss, altered vascular permeability and loss of central vision. Currently there is no effective treatment available except gene replacement therapy has shown promise in a few patients with specific gene defects. There is an urgent need to develop therapies that offer generic neuro-and vascular-protective effects with non-invasive intervention. Here we explored the potential of systemic administration of pluripotent bone marrow-derived mesenchymal stem cells (MSCs) to rescue vision and associated vascular pathology in the Royal College Surgeons (RCS) rat, a well-established animal model for RP.

METHODOLOGY/PRINCIPAL FINDINGS:

Animals received syngeneic MSCs (1x10(6) cells) by tail vein at an age before major photoreceptor loss. Principal results: both rod and cone photoreceptors were preserved (5-6 cells thick) at the time when control animal has a single layer of photoreceptors remained; Visual function was significantly preserved compared with controls as determined by visual acuity and luminance threshold recording from the superior colliculus; The number of pathological vascular complexes (abnormal vessels associated with migrating pigment epithelium cells) and area of vascular leakage that would ordinarily develop were dramatically reduced; Semi-quantitative RT-PCR analysis indicated there was upregulation of growth factors and immunohistochemistry revealed that there was an increase in neurotrophic factors within eyes of animals that received MSCs.

CONCLUSIONS/SIGNIFICANCE:

These results underscore the potential application of MSCs in treating retinal degeneration. The advantages of this non-invasive cell-based therapy are: cells are easily isolated and can be expanded in large quantity for autologous graft; hypoimmunogenic nature as allogeneic donors; less controversial in nature than other stem cells; can be readministered with minor discomfort. Therefore, MSCs may prove to be the ideal cell source for auto-cell therapy for retinal degeneration and other ocular vascular diseases.


 

 

Clin Invest. 2010 September 1; 120(9): 3012–3021.


PMCID: PMC2929728

Stemming vision loss with stem cells

Valentina Marchetti,1 Tim U. Krohne,1 David F. Friedlander,2 and Martin Friedlander1

1Department of Cell Biology, The Scripps Research Institute, La Jolla, California, USA. 2School of Medicine, Vanderbilt University, Nashville, Tennessee, USA.

Address correspondence to: Martin Friedlander, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92014, USA. Phone: 858.784.9138; Fax: 858.784.9135; E-mail: friedlan@scripps.edu.

Abstract

Dramatic advances in the field of stem cell research have raised the possibility of using these cells to treat a variety of diseases. The eye is an excellent target organ for such cell-based therapeutics due to its ready accessibility, the prevalence of vasculo- and neurodegenerative diseases affecting vision, and the availability of animal models to demonstrate proof of concept. In fact, stem cell therapies have already been applied to the treatment of disease affecting the ocular surface, leading to preservation of vision. Diseases in the back of the eye, such as macular degeneration, diabetic retinopathy, and inherited retinal degenerations, present greater challenges, but rapidly emerging stem cell technologies hold the promise of autologous grafts to stabilize vision loss through cellular replacement or paracrine rescue effects.


 

Korean J Ophthalmol. 2011 Aug;25(4):268-74. Epub 2011 Jul 22.

Modulation of retinal wound healing by systemically administered bone marrow-derived mesenchymal stem cells.

Chung JK, Park TK, Ohn YH, Park SK, Hong DS.

Source

Department of Ophthalmology, University Hospital, Soonchunhyang University College of Medicine, #1174 Jung-dong, Wonmi-gu, Bucheon, Korea.

Abstract

PURPOSE:

To evaluate whether systemically injected bone marrow-derived mesenchymal stem cells (MSCs) can be incorporated into neuroretinal tissues and play an important role in retinal wound healing in the laser-induced retinal trauma model.

METHODS:

Retinotomies were made by applying an Nd:YAG laser to rat retina. On the first day after the injuries, cell suspensions that were obtained from the same line of rat (containing 1 × 10(6) green fluorescence protein [GFP]-marked bone marrow-derived MSCs) were injected through a tail vein in the experimental group and phosphate buffer solution (PBS) was injected in the same way in the control group. Fundus photographs were taken serially for fundus examination and eyeballs were enucleated for histological studies that were conducted at five and seven weeks after MSC and PBS injection. After the tissues were prepared, the retinotomy sites were observed with routine histological staining and confocal microscopy.

RESULTS:

Retinal detachment resolved in the experimental group, whereas it progressed in the control group. The retinotomy sites closed partially with identifiable GFP positive cells 5 weeks after MSC injection. At 7 weeks after MSC injection, complete healing without retinal detachment and plentiful GFP positive cells were observed at the transitional zone between damaged and normal retina.

CONCLUSIONS:

Systemically administered GFP-marked MSCs may be incorporated into the neuroretinal tissues and play an important role in the wound modulation of physically damaged retinal tissues.


`

J Biomed Biotechnol. 2012; 2012: 480289.

Published online 2012 February 13. doi:  10.1155/2012/480289

PMCID: PMC3303614

Autism Spectrum Disorders: Is Mesenchymal Stem Cell Personalized Therapy the Future?

Dario Siniscalco, 1, 2 , * Anna Sapone, 3, 4 , Alessandra Cirillo, 5 Catia Giordano, 1 Sabatino Maione, 1 and Nicola Antonucci 6

1Division of Pharmacology “L. Donatelli”, Department of Experimental Medicine, Second University of Naples, Via S. Maria di Costantinopoli, 16-80138 Napoli, Italy

2Centre for Autism, La Forza del Silenzio, Caserta, 80138 Naples, Italy

3Department of Internal and Experimental Medicine “Magrassi-Lanzara”, Second University of Naples, 80138 Naples, Italy

4Center for Celiac Research and Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA

5Division of Biotechnology and Molecular Biology “A. Cascino”, Department of Experimental Medicine, Second University of Naples, 80138 Naples, Italy

6Biomedical Centre for Autism Research and Treatment, 70122 Bari, Italy

*Dario Siniscalco: dariosin@uab.edu

Academic Editor: Ken-ichi Isobe

Received July 11, 2011; Accepted September 29, 2011.

Copyright © 2012 Dario Siniscalco et al.

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Autism and autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental disorders. They are enigmatic conditions that have their origins in the interaction of genes and environmental factors. ASDs are characterized by dysfunctions in social interaction and communication skills, in addition to repetitive and stereotypic verbal and nonverbal behaviours. Immune dysfunction has been confirmed with autistic children. There are no defined mechanisms of pathogenesis or curative therapy presently available. Indeed, ASDs are still untreatable. Available treatments for autism can be divided into behavioural, nutritional, and medical approaches, although no defined standard approach exists. Nowadays, stem cell therapy represents the great promise for the future of molecular medicine. Among the stem cell population, mesenchymal stem cells (MSCs) show probably best potential good results in medical research. Due to the particular immune and neural dysregulation observed in ASDs, mesenchymal stem cell transplantation could offer a unique tool to provide better resolution for this disease.

1. Autism Spectrum Disorders

Autism and autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental disorders [1]. They are enigmatic conditions that have their origins in the interaction of genes and environmental factors. ASDs are characterized by dysfunctions in social interaction and communication skills, in addition to repetitive and stereotypic verbal and nonverbal behaviours [2, 3]. Several biochemical events are associated with ASDs: oxidative stress; endoplasmic reticulum stress; decreased methylation capacity; limited production of glutathione; mitochondrial dysfunction; intestinal dysbiosis; increased toxic metal burden; immune dysregulation; immune activation of neuroglial cells [4]. The exact aetiology of ASDs is unknown, likely it results from a complex combination of genetic, environmental, and immunological factors [5, 6]. This heritable disorder derives from genetic variations in multiple genes [7], making its treatment particularly difficult. Environment (i.e., air pollution, organophosphates, and heavy metals) also contributes to the incidence of ASDs [8].

Frequency of these disorders is increasing: 56% reported increase in paediatric prevalence between 1991 and 1997 [9] until present rates of about 60 cases per 10,000 children, according to Center for Disease Control [10, 11]. ASDs are increasingly being recognized as a public health problem [12]. Pathophysiology and defined mechanisms of pathogenesis of autism remain still unclear. There are no drugs effective for treatment of core symptoms of ASDs [10]. Indeed, ASDs are still untreatable. Current available treatments for autism can be divided into behavioural, nutritional, and pharmacological options, in addition to individual and family psychotherapy and other nonpharmacologic interventions [13]. However, no defined standard approach exists [14]. Pharmacological approaches are direct towards neuropsychiatric disorders coassociated with ASDs. Psycho-stimulants, alpha-2 agonists, beta blockers, lithium, anticonvulsant mood stabilizers, atypical antipsychotics, traditional antipsychotics, selective serotonin reuptake inhibitors, antidepressants, and antipsychotics, are drugs commonly prescribed [1416]. Catatonia is treated with lorazepam and bilateral electroconvulsive therapy [17]. Selective serotonin reuptake inhibitors are prescribed for the treatment of depression, anxiety, and obsessive-compulsive ASD-associated behaviours [2].

Other nonpsychotropic drugs which are supported by at least 1 or 2 prospective randomized controlled trials or 1 systematic review include melatonin, acetylcholinesterase inhibitors, naltrexone, carnitine, tetrahydrobiopterin, vitamin C, hyperbaric oxygen treatment, immunomodulation and anti-inflammatory treatments, oxytocin, and even music therapy and vision therapy [18].

Alternative and complementary treatments, not sufficiently supported by medical literature, include herbal remedies, vitamin and mineral therapies, piracetam, elimination diets, chelation, cyproheptadine, famotidine, glutamate antagonists, special dietary supplements, acupuncture, neurofeedback, and sensory integration training [14, 19, 20]. On the other hand, behavioural treatment could represent the effective intervention strategy for autism [2123]. A plethora of behavioural strategies and social skill trainings have been used [2426]. However, it has been demonstrated that no definitive behavioural intervention completely improves all symptoms for all ASD patients [27, 28].

Summarizing, all these therapies indicate that further research is needed to better address treatment of several medical conditions experienced by ASD patients [29].

2. Mesenchymal Stem Cells

Nowadays, stem cell therapy represents the great promise for the future of molecular medicine. The progression of several diseases can be slowed or even blocked by stem cell transplantation [30].

Among the stem cell population, mesenchymal stem cells (MSCs) show probably best potential good results in medical research [3133]. These cells are nonhematopoietic stem cells having a multilineage potential, as they have the capacity of differentiating into both mesenchymal and nonmesenchymal lineages. MSCs are a population of progenitor cells of mesodermal origin found principally in the bone marrow of adults, giving rise to skeletal muscle cells, blood, fat, vascular, and urogenital systems, and to connective tissues throughout the body [3436]. According to the International Society of Cellular Therapy, MSCs are defined by the following minimal set of criteria: (1) grown in adherence to plastic surface of dishes when maintained in standard culture conditions; (2) express cytospecific cell surface markers, that is, CD105, CD90, and CD73, to be negative for other cell surface markers, that is, CD45, CD34, CD14, and CD11b; (3) possess the capacity to differentiate into mesenchymal lineages, under appropriate in vitro conditions [37]. MSCs can be isolated from different tissues other than bone marrow: adipose tissue, liver, tendons, synovial membrane, amniotic fluid, placenta, umbilical cord, and teeth. MSCs show a high expansion potential, genetic stability, stable phenotype, high proliferation rate as adherent cells, and self-renew capacity and can be easily collected and shipped from the laboratory to the bedside and are compatible with different delivery methods and formulations [38, 39]. In addition, MSCs have two other extraordinary properties: they are able to migrate to sites of tissue injury, where they are able to inhibit the release of proinflammatory cytokines and have strong immunosuppressive activity that renders them a useful tool for successful autologous, as well as heterologous, transplantations without requiring pharmacological immunosuppression [4043]. Besides, MSCs are easily isolated from a small aspirate of bone marrow and expanded with high efficiency [44]. Given that MSCs are multipotent cells with a number of potential therapeutic applications, and they represent a future powerful tool in regenerative medicine, including ASDs. Mesenchymal stem cells could be transplanted directly without genetic modification or pretreatments. They simply eventually differentiate according to cues from the surrounding tissues and do not give uncontrollable growth or tumours. In clinical application, there is no problem with immune rejection because of their in vivo immunosuppressive properties [45, 46]. In addition, MSCs can readily be isolated from the patients requiring transplant or from their parents. There is also no tumour formation on transplantation [47]. No moral objection or ethical controversies are involved [48].

In principle, mesenchymal stem cells can act through several possible mechanisms, that is, stimulating the plastic response in the host damaged tissue, secreting survival-promoting growth factors, restoring synaptic transmitter release by providing local reinnervations, integrating into existing neural and synaptic network, and reestablishing functional afferent and efferent connections [49]. Since MSCs have the capability to produce a large array of trophic and growth factors both in vivo and in vitro. (MSCs constitutively secrete interleukins (IL)-6, IL-7, IL-8, IL-11, IL-12, IL-14, IL-15, macrophage colony-stimulating factor, Flt-3 ligand, and stem-cell factor [50]). A more reasonable explanation for the functional benefit derived from MSC transplantation is their paracrine activity, by which these cells are able to produce factors that activate endogenous restorative mechanisms within injured tissues contributing to recovery of function lost as a result of lesions [49, 51].

3. Autism, Personalized Therapy through Mesenchymal Stem Cells

MSCs have a strong long-lasting immunosuppressive capacity [52]. This extraordinary property is mediated via soluble factors. MSCs are able to inhibit the proliferation of CD8+ and CD4+ T lymphocytes and natural killer (NK) cells, to suppress the immunoglobulin production by plasma cells, to inhibit the maturation of dendritic cells (DCs) and the proliferation of regulatory T cells [53]. It has been demonstrated that MSCs are also able to inhibit T lymphocyte pro-inflammatory cytokine production in vitro [54, 55], as well as in vivo [56]. Their ability to modulate the immune system opens a wide range of cell-mediated applications, not only for autoimmune diseases and graft-versus-host disease. Due to the particular immune system dysregulation observed in ASDs [57, 58], mesenchymal stem cell transplantation could offer a unique tool to provide better resolution for this disease. Indeed, in ASDs pathogenesis, innate and adaptive immunity changes have been reported [59]. ASD patients show an imbalance in CD3+, CD4+, and CD8+ T cells, as well as in NK cells. In addition, peripheral blood mononuclear cells (PBMCs) extracted from ASD patients are able to overproduce IL-1β resulting in long-term immune alterations [60]. MSC-mediated immune suppressive activity could restore this immune imbalance (Figure 1). Indeed, MSC immunoregulatory effects strongly inhibit T-cell recognition and expansion by inhibiting TNF-α and INF-γ production and increasing IL-10 levels [51].

It has been demonstrated that in postmortem brains from ASD patients there is evidence of abnormal functioning and cerebellum alterations [6163]. Indeed, ASD subjects show a decreased number of Purkinje cells in the cerebellum [64]. These changes could reflect defective cortical organization in ASDs development. In addition, autism is associated with dysregulation in the maturation and plasticity of dendritic spine morphology [65]. Restoring injured brain functioning could be achieved by stem-cell-based cell replacement [66]. Indeed, transplanted MSCs are able to promote synaptic plasticity and functional recovery and rescue cerebellar Purkinje cells [67, 68]. Challenging newest study from Deng et al. suggests that granulocyte colony-stimulating factor (G-CSF) is able to mobilize MSCs into peripheral blood. These mobilized MSCs are incorporated and integrate into damaged brain in craniocerebral injured mice, ameliorating the effect of trauma [69]. It is noteworthy that MSC ability to migrate to the sites of injury and participate in the repair process is a key issue in tissue repair [70]. Also by this way, MSC therapy could restore the altered brain organization seen in autistic subjects.

A key dilemma in stem-cell-based therapy for autism treatment is whether endogenous or exogenous MSC administration is the best way of stem cell delivery. Endogenous strategy could be limited by the availability of MSCs. Exogenous MSCs could show low rate of engraftment to provide cellular replacement. It is unclear if differentiated cells are able to develop functional interconnections with the intrinsic cells of the recipient host [49]. Controversy, few exogenous MSCs are able to exert paracrine activity. Indeed, exogenously applied MSCs have been shown to home to injured tissues and repair them by producing chemokines, or by cell or nuclear fusion with host cells [71]. On the other hand, exogenous culture-expanded MSCs could address endogenous MSCs in order to activate them and guide intrinsic repair [72]. In addition, exogenous delivery bypasses surgical intervention on the autistic child.

Cellular therapy could represent a new frontier in the treatment of several diseases. Despite the fact that MSCs have been enrolled in several clinical trials, long-term safety of MSC-based therapies is not yet well established; this fact could be one major limitation to clinical translation [73]. At the present, there are no preclinical studies on the use of MSCs in ASD models. There is just one clinical trial (NCT01343511 http://www.clinicaltrial.gov/) concerning the safety and efficacy of human umbilical cord mesenchymal stem cells (hUC-MSCs) and human cord blood mononuclear cells (hCB-MNCs) transplantation in patients with autism by Shenzhen Beike Bio-Technology Co., China. Results are not yet posted.

However, personalized stem cell therapy will be the most effective treatment for a specific autistic child, opening a new era in autism management in the next future.


Clinical Trials for Mesenchymal Stem Cells: below are just a few clinical trials that are current and relevant to mesenchymal stem cell treatments. These are registered trials, and there are also many unregistered trials being undertaken around the world. The number of registered trials is rapidly expanding. We will endevour to periodically update this list.

 

 

Intravenous Stem Cells After Ischemic Stroke,

Phase 2,

ClinicalTrials.gov Identifier:

NCT00875654

Detailed Description:

Stroke is the leading cause of acquired adult disability. Except the hospitalization in stroke units, only thrombolysis has been shown to be efficient to treat acute ischemic stroke in the first three hours after the onset. Increasing brain plasticity after stroke represents an important alternative strategy. Cell therapy provides a functional improvement after cerebral ischemia in rodent models. This "restorative" therapy aims to replace destroyed cerebral tissue with a stem cells graft. Despite these encouraging experiments, we do not know yet the best way of administration of the stem cells, the best dose and the optimal delay of the graft. The pioneer clinical studies failed to reproduce this benefit for patients probably because of the limited number of studied patients. Therefore, more translational studies are needed to improve our knowledge in this promising field. Among different cell sources, mesenchymal (or stromal) stem cells (MSC) derived from bone marrow offer the advantage of arising from a non tumoral and no modified source and are not sources of immunological or ethical problems.

Our research project involves a development of cell therapy in a phase IIa clinical trial of feasibility and safety in patients (randomised, controlled, open, with 3 parallel groups).


  

Umbilical Cord Mesenchymal Stem Cells Infusion for Ulcerative Colitis

Phase 1
Phase 2
ClinicalTrials.gov Identifier: NCT01221428

Detailed Description:

Ulcerative colitis is characterized as chronic and nonspecific inflammation of gastroenteritis tractNowadaysetiology and pathogenesis of UC have been unclearRecent basic research has been revealed that stem cell can settle down in epithelium of gastroenteritis tractwhich provide a hope for treating the disease.We hope umbilical cord Mesenchymal Stem Cells could not only address the need for epithelial cell replacement but also control of the autoimmune response to mocous membrane of colon.

  


  

Umbilical Cord Mesenchymal Stem Cells Infusion for Initial Type 1 Diabetes Mellitus

Phase 1
Phase 2

ClinicalTrials.gov Identifier:

NCT01219465

Detailed Description:

Type 1 diabetes mellitus (T1DM)is characterized by the autoimmune destruction of the pancreatic β cells.Patients require multiple daily insulin injections throughout their lives as well as close monitoring of their diet and blood sugar levels to prevent complications. The investigators hope umbilical cord Mesenchymal Stem Cells could not only address the need for β-cell replacement but also control of the autoimmune response to β cells.


  

  

Clinical Trial on The Use of Autologous Bone Marrow Stem Cells in Amyotrophic Lateral Sclerosis (Extension CMN/ELA)

Phase 1
Phase 2

ClinicalTrials.gov Identifier:

NCT01254539

Detailed Description:

Patients with Amyotrophic Lateral Sclerosis (ALS) typically endure a progressive paralysis due to the continued loss of motoneurons that leads them to death in less than 5 years. No treatment has changed its natural history. Intraspinal injections of bone marrow mononuclear cells (MNC) have been able to ameliorate the course of ALS in murine models, acting as pumps of trophic factors that keep the motoneurons functional. Moreover, the clinical trial (Study NCT00855400 on www.ClinicalTrials.gov) conducted by our research group to determine the safety and efficacy of Autologous Stem Cell transplantation in Amyotrophic Lateral Sclerosis in humans, found that this procedure is feasible and safe. Continuing with that study, we have designed a phase I/II clinical trial to check the feasibility of the intraspinal and intrathecal infusion of autologous bone marrow stem cells.


  

The Clinical Trial on the Use of Umbilical Cord Mesenchymal Stem Cells in Amyotrophic Lateral Sclerosis

Phase 2

ClinicalTrials.gov Identifier:

NCT01494480


  

Evaluation of Autologous Mesenchymal Stem Cell Transplantation (Effects and Side Effects) in Multiple Sclerosis

Phase 1
Phase 2

ClinicalTrials.gov Identifier:

NCT01377870

Purpose

Multiple sclerosis is a multifocal inflammatory disease of the central nervous system which affects young individuals and causes paralysis of the limbs, sensation, visual and sphincter problems. The disease is caused by an autoimmune mechanism, ie the immune system produces antibodies and cells which attack the self myelin antigens, causing therefore demyelination. The disease is clinically evident with relapses of neurological disability due to the dysfunction of the areas (plaques of multiple sclerosis) in which damage of myelin occurs. Disability can accumulate with time and the disease enters a progressive phase due to damage of the axons and irreversible neurodegeneration. Although, effective immunotherapies exist which downregulate the autoimmune anti-myelin reactivity and reduce the rate of relapses of MS (like Copaxone and interferons), there is no effective means today to stop the progression of disability and induce rebuilding of the destroyed myelin.Adult bone marrow derived stromal cells (MSC) were shown to induce similar (to the neuronal stem cells) immunomodulatory and neuroregenerative effects and were shown in our laboratory to induce neuroprotection in the animal model of chronic experimental autoimmune encephalomyelitis (EAE). These bone marrow derived MSCs offer practical advantages for clinical therapeutic applications, since they can be obtained from the adult bone marrow and therefore the patient can be the donor for himself, without any danger for rejection of the cells. In addition, MSCs carry a safer profile and are less prone to malignant transformation.

Our center will perform a clinical trial with intra venous transplantation of bone marrow derived mesenchymal stem cell.our purpose is to evaluate the safety and feasibility of cell transplantation after 1year following up.

Detailed Description:

In the clinical trial 30 patients with multiple sclerosis who are drug resistance will take apart.Based on inclusion and exclusion criteria patients are chosen.Bone marrow aspiration will be done for all of them under local anesthesia.Patients are randomly divided in 2 groups:case and control. Then mesenchymal stem cells which are separated and prepared will be transplanted by intravenous injection to the patients in case group and the cells which obtain from patients in control group are frozen and inject after 6 months. Patients will be followed by Evaluation of EDSS MSFC RAO Test brain and cervical MRI and quality of life questionnaire after 1th 3th 6th and 12th months after transplantation.all these tests will be done before transplantation as basic evaluation


  

  

Autologous Mesenchymal Stem Cells From Adipose Tissue in Patients With Secondary Progressive Multiple Sclerosis (CMM/EM/2008)

ClinicalTrials.gov Identifier:

NCT01056471

Phase 1
Phase 2

Purpose

The main purpose of this study is to evaluate the safety and feasibility of regenerative therapy with mesenchymal stem cells from adipose tissue, administered intravenously in patients with secondary progressive multiple sclerosis who do not respond to treatment.


 

Stem Cells in Rapidly Evolving Active Multiple Sclerosis

ClinicalTrials.gov Identifier:

NCT01606215

Phase 1
Phase 2

Purpose

This is a randomised, double-blind crossover study to study the effect of intravenous treatment with autologous (derived from the individuals themselves) mesenchymal stem cells (MSCs)in patients with multiple sclerosis (MS).

Current treatments for MS target the immune system and are not curative. There is much interest in MSCs as they have the potential to not only affect the immune system but may also promote repair. This study will use MSCs that are harvested from the bone marrow and grown for up to 52 days before being given back to the person from whom they were harvested. This avoids any chemotherapy so is therefore safer than other types of stem cells. In this crossover study, everyone will receive their own stem cells back but in half it will be delayed by 24 weeks.

The primary outcomes are to check that the procedure is safe and to measure any changes on the MRI at 24 weeks. Other more exploratory measures will try to assess effects on repair in the CNS.


  

  

Mesenchymal Stem Cells for Multiple Sclerosis

ClinicalTrials.gov Identifier:

NCT01730547

Phase 1
Phase 2

Purpose

The aim of the study is to evaluate the safety and efficacy of autologous mesenchymal stromal cells as treatment for Multiple Sclerosis.




  

Mesenchymal Stem Cells for the Treatment of MS

ClinicalTrials.gov Identifier:

NCT00781872

Phase 1
Phase 2

Purpose

Multiple sclerosis is a multifocal inflammatory disease of the central nervous system which affects young individuals and causes paralysis of the limbs, sensation, visual and sphincter problems. The disease is caused by an autoimmune mechanism, ie the immune system produces antibodies and cells which attack the self myelin antigens, causing therefore demyelination. The disease is clinically evident with relapses of neurological disability due to the dysfunction of the areas (plaques of multiple sclerosis) in which damage of myelin occurs. Disability can accumulate with time and the disease enters a progressive phase due to damage of the axons and irreversible neurodegeneration. Although, effective immunotherapies exist which downregulate the autoimmune anti-myelin reactivity and reduce the rate of relapses of MS (like Copaxone and interferons), there is no effective means today to stop the progression of disability and induce rebuilding of the destroyed myelin (re-myelination). Neuronal stem cells were shown to possess the ability to restore neuronal activity and produce new neurons through transdifferentiation. Various other types of stem cells were tested in animal models with promising results, revealing a potential for restoration of the neurological function in neuroimmune and neurodegenerative conditions and in central nervous system traumatic injury. Adult bone marrow derived stromal cells (MSC) were shown to induce similar (to the neuronal stem cells) immunomodulatory and neuroregenerative effects and were shown in our laboratory to induce neuroprotection in the animal model of chronic experimental autoimmune encephalomyelitis (EAE). These bone marrow derived MSCs offer practical advantages for clinical therapeutic applications, since they can be obtained from the adult bone marrow and therefore the patient can be the donor for himself, without any danger for rejection of the cells. In addition, MSCs carry a safer profile and are less prone to malignant transformation.

Our initial clinical experience with 10 patients with ALS and 10 with multiple sclerosis show that intravenous and intrathecal administration of MSCs is feasible and safe.

In this study we propose an explorative protocol with the injection of MSCs (both intrathecally and intravenously) in patients with MS, in an effort to prevent further neurodegeneration through neuroprotective mechanisms and induce neuroregeneration and restoration of neuronal function. This will be a phase I/II study.

The primary endpoint will be to further evaluate the safety and feasibility of the treatment with MSC infusions, in MS patients. Additionally, the migration ability of the transplanted cells will be evaluated by tagging MSCs with the superparamagnetic iron oxide particle (Feridex) (an FDA approved cell tracking drug) for detection by MRI. MRI of the brain and spinal cord will be performed at weeks 1, 4, 12 and 24 to detect the migration of the stem cells. Clinically the patients will be followed by monthly evaluations of the MS functional rating scale (EDSS) scale. The MRI, will be also used to evaluate changes in the total volume of lesions in the brain and the degree of atrophy.

Significance: Our center has performed the first clinical trial with intrathecal and intravenous injection of adult stem cells in MS and ALS patients and has gained experience during the last 3 years with this type of stem cells treatment. After having evaluated the safety and feasibility issues, we intent to proceed to the second stage, to evaluate the migration ability of those cells (their ability to reach the affected motor areas of the CNS gray matter, by tracking them with a paramagnetic material and visualize them by MRI), and evaluate indications of clinical efficacy. This project may provide information for possible therapeutic uses of this type of bone marrow adult stem cells in MS and ALS but may also serve as a pilot platform and pave the path for future applications of various types of stem cells in neurodegerative diseases in general.

  


  

Autologous Mesenchymal Stem Cells From Adipose Tissue in Patients With Secondary Progressive Multiple Sclerosis

ClinicalTrials.gov Identifier:

NCT01056471

Phase 1
Phase 2

Purpose

The main purpose of this study is to evaluate the safety and feasibility of regenerative therapy with mesenchymal stem cells from adipose tissue, administered intravenously in patients with secondary progressive multiple sclerosis who do not respond to treatment.




  

Mesenchymal Stem Cell Transplantation in MS

ClinicalTrials.gov Identifier:

NCT01228266

Phase 2

  Purpose

The study is a randomized Phase II study, masked and crossed-over with placebo to evaluate the safety and tolerability of autologous mesenchymal stem cell transplantation in patients with active multiple sclerosis

  


  

Study to Assess the Safety and Effects of Autologous Adipose-Derived Stromal Cells Delivered Into Patients With Multiple Sclerosis

ClinicalTrials.gov Identifier:

NCT01453764

Phase 1
Phase 2

Purpose

The intent of this clinical study is to answer the questions:

  1. Is the proposed treatment safe
  2. Is treatment effective in improving the disease pathology of patients with Multiple Sclerosis and clinical outcomes?


  

  

Mesenchymal Cells From Autologous Bone Marrow, Administered Intravenously in Patients Diagnosed With Multiple Sclerosis

ClinicalTrials.gov Identifier:

NCT01745783

Phase 1
Phase 2

Purpose

This is a phase I / II for the evaluation of the safety and feasibility of intravenous infusion of mesenchymal cells from autologous bone marrow in patients with Multiple Sclerosis.

Intravenous administration of autologous mesenchymal cells of bone marrow is feasible and safe and can be effective in treating patients suffering from multiple sclerosis


 

Treatment of Patients With Newly Onset of Type 1 Diabetes With Mesenchymal Stem Cells

ClinicalTrials.gov Identifier: NCT01068951

The main hypothesis of the investigators study is that the development of autoimmune diabetes may be halted att diagnosis by the immune modulatory properties of mesenchymal stem cells.

Biological: Mesenchymal stem cells

Autologous transplantation of the patients own mesenchymal stem cells (approximately 2 x 106 cells/kg body weight) intravenously


 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

© New Zealand Stem Cell Cinic 2011; NZ Stem Cell Clinic, Auckland, Christchurch. PO Box 36088, Merivale, Christchurch, New Zealand. Ph/fx +64 3 3555 712, info@stemcelltreatment.co.nz