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Stemcell Research & Evidence - Neurologic Conditions
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Stem cell potential in Parkinson's disease
Biochim Biophys Acta. 2011 Jan;1812(1):1-11.
Source
Laboratory of Molecular and Stem Cell Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 156-756, South Korea.
hyunjungkim@cau.ac.kr
Abstract
Parkinson's disease (PD) involves the loss of dopamine (DA) neurons, making it the most expected neurodegenerative disease to be treated by cell replacement therapy. Stem cells are a promising source for cell replacement therapy due to their ability to self-renew and their pluripotency/multipotency that allows them to generate various types of cells. However, it is challenging to derive midbrain DA neurons from stem cells. Thus, in this review, I will discuss the molecular factors that are known to play critical roles in the generation and survival of DA neurons. The developmental process of DA neurons and functions of extrinsic soluble factors and homeodomain proteins, forkhead box proteins, proneural genes, Nurr1 and genes involved in epigenetic control are discussed. In addition, different types of stem cells that have potential for future cell replacement therapy are reviewed.
Ageing and neurodegenerative diseases
Ageing Res Rev. 2010 Nov;9 Suppl 1:S36-46.
Source
Department of Neurology, Zhongxiao Branch, Taipei City Hospital/No 87, Tongde Rd, Nangang Dist, Taipei City 115, Taiwan.
Abstract
Ageing, which all creatures must encounter, is a challenge to every living organism. In the human body, it is estimated that cell division and metabolism occurs exuberantly until about 25 years of age. Beyond this age, subsidiary products of metabolism and cell damage accumulate, and the phenotypes of ageing appear, causing disease formation. Among these age-related diseases, neurodegenerative diseases have drawn a lot of attention due to their irreversibility, lack of effective treatment, and accompanied social and economical burdens. In seeking to ameliorate ageing and age-related diseases, the search for anti-ageing drugs has been of much interest. Numerous studies have shown that the plant polyphenol, resveratrol (3,5,4'-trihydroxystilbene), extends the lifespan of several species, prevents age-related diseases, and possesses anti-inflammatory, and anti-cancer properties. The beneficial effects of resveratrol are believed to be associated with the activation of a longevity gene, SirT1. In this review, we discuss the pathogenesis of age-related neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and cerebrovascular disease. The therapeutic potential of resveratrol, diet and the roles of stem cell therapy are discussed to provide a better understanding of the ageing mystery.
Implications for cell-based therapies in Parkinson's disease
Biol Blood Marrow Transplant. 2010 Nov;16(11):1530-40.
Source
Institute of Science, Clinica Alemana Universidad del Desarrollo, Santiago, Chile.
Abstract
It is thought that the ability of human mesenchymal stem cells (hMSC) to deliver neurotrophic factors might be potentially useful for the treatment of neurodegenerative disorders. The aim of the present study was to characterize signals and/or molecules that regulate brain-derived neurotrophic factor (BDNF) protein expression/delivery in hMSC cultures and evaluate the effect of epigenetically generated BDNF-secreting hMSC on the intact and lesioned substantia nigra (SN). We tested 4 different culture media and found that the presence of fetal bovine serum (FBS) decreased the expression of BDNF, whereas exogenous addition of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) to serum-free medium was required to induce BDNF release (125 ± 12 pg/day/10⁶ cells). These cells were called hM(N)SC. Although the induction medium inhibited the expression of alpha smooth muscle actin (ASMA), an hMSC marker, and increased the nestin-positive subpopulation of hMSC cultures, the ability to express BDNF was restricted to the nestin-negative subpopulation. One week after transplantation into the SN, the human cells integrated into the surrounding tissue, and some showed a dopaminergic phenotype. We also observed the activation of Trk receptors for neurotrophic factors around the implant site, including the BDNF receptor TrkB. When we transplanted these cells into the unilateral lesioned SN induced by striatal injection of 6-hydroxydopamine (6-OHDA), a significant hypertrophy of nigral tyrosine hydroxylase (TH)(+) cells, an increase of striatal TH-staining and stabilization of amphetamine-induced motor symptoms were observed. Therefore, hMSC cultures exposed to the described induction medium might be highly useful as a vehicle for neurotrophic delivery to the brain and specifically are strong candidates for future therapeutic application in Parkinson's disease.
A rat model of Parkinson's disease
Neurochem Res. 2010 Oct;35(10):1522-9.
Ming Li, Shi-Zhong Zhang, Yan-Wu Guo, Ying-qian Cai, Zhong-jie Yan, Zhihao Zou, Xiao-Dan Jiang, Yi-Quan Ke, Xu-ying He, Zeng-liang Jin, Guo-hui Lu, Dao-qing Su
Source
Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
liming1142@yahoo.com.cn
Abstract
Mesenchymal stem cells are capable of differentiating into dopaminergic-like cells, but currently no report has been available to describe the induction of human umbilical vein mesenchymal stem cells (HUVMSCs) into dopaminergic-like cells. In this study, we induced HUVMSCs in vitro into neurospheres constituted by neural stem-like cells, and further into cells bearing strong morphological, phenotypic and functional resemblances with dopaminergic-like cells. These HUVMSC-derived dopaminergic-like cells, after grafting into the brain of a rat model of Parkinson's disease (PD), showed a partial therapeutic effect in terms of the behavioral improvement. Nerve growth factor was reported to improve the local microenvironment of the grafted cells, and we therefore further tested the effect of dopaminergic-like cell grafting combined with nerve growth factor (NGF) administration at the site of cell transplantation. The results showed that NGF administration significantly promoted the survival of the grafted cells in the host brain and enhanced the content of dopaminergic in the local brain tissue. Behavioral test demonstrated a significant improvement of the motor function of the PD rats after dopaminergic-like cell grafting with NGF administration as compared with that of rats receiving the cell grafting only. These results suggest that transplantation of the dopaminergic-like cells combined with NGF administration may represent a new strategy of stem cell therapy for PD.
Rat mesenchymal stem cells as vehicles for delivery of neurotrophins to the Parkinsonian rat brain
Brain Res. 2010 Nov 4;1359:33-43.
Source
The Department of Pharmacology & Therapeutics, National University of Ireland, Galway, Ireland; National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Ireland.
Abstract
Issues related to the intra-cerebral delivery of glial cell line-derived neurotrophic factor (GDNF) have hampered its progression as a neuroprotective therapy for Parkinson's disease. Ex vivo gene therapy, where cells are virally transduced in vitro to produce a specific protein, may circumvent some of the problems associated with direct delivery of this neurotrophin to the brain. In this regard, bone marrow-derived mesenchymal stem cells (MSCs) offer an ideal cell source for ex vivo gene therapy because they are easily isolated from autologous sources, they are amenable to viral transduction and expansion in vitro, and they are hypoimmunogenic and non-tumourigenic in the brain. Thus the aim of this study was to determine the neurotrophic capacity of GDNF-transduced MSCs in a rat model of Parkinson's disease. Rats received intrastriatal transplants of GDNF-transduced MSCs 4days prior to induction of an intrastriatal 6-hydroxydopamine lesion. Quantitative tyrosine hydroxylase immunohistochemical staining revealed that GDNF-transduced MSCs were capable of inducing a pronounced local trophic effect in the denervated striatum which was evident by sprouting from the remaining dopaminergic terminals towards the neurotrophic milieu created by the transplanted cells. This strengthens the candidacy of MSCs as vehicles to deliver neurotrophins to the Parkinsonian brain.
Stem cells and neurological diseases
Gene Ther. 2011 Jan;18(1):1-6.
Source
Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London, UK.
stefanie.gogel@kcl.ac.uk
Abstract
The central nervous system has limited capacity of regenerating lost tissue in slowly progressive, degenerative neurological conditions such as Parkinson's disease (PD), Alzheimer's disease or Huntington's disease (HD), or in acute injuries resulting in rapid cell loss for example, in cerebrovascular damage (for example, stroke) or spinal cord injury. Although the adult brain contains small numbers of stem cells in restricted areas, they do not contribute significantly to functional recovery. Transplantation of stem cells or stem cell-derived progenitors has long been seen as a therapeutic solution to repair the damaged brain. With the advent of the induced pluripotent stem cells technique a new and potentially better source for transplantable cells may be available in future. This review aims to highlight current strategies to replace lost cellular populations in neurodegenerative diseases with the focus on HD and PD and traumatic brain injuries such as stroke, discussing many of the technical and biological issues associated with central nervous system cell transplantation.
Translation of stem cell therapy for neurological diseases
Transl Res. 2010 Sep;156(3):155-60.
Source
Department of Neurology, University of Leipzig, Leipzig, Germany.
Abstract
"Regenerative medicine" hopefully will provide novel therapies for diseases that remain without effective therapy. This development is also true for most neurodegenerative disorders including Alzheimer's disease, Huntington's disease, or Parkinson's disease. Transplantation of new neurons to the brain has been performed in Parkinson's disease and in Huntington's disease. The restoration of dopaminergic neurons in patients with Parkinson's disease via implantation of embryonic midbrain tissue was taken from animal experiments to clinical applications, showing a limited efficacy. Clinical trials in patients with Huntington's disease using fetal striatal tissue currently are underway. Today, it seems possible to generate functional dopaminergic or striatal neurons form a variety of stem cells including embryonic or neural stem cells as well as induced pluripotent stem cells. First clinical trials using neural stem cell or embryonic-stem-cell-derived tissue are approved or already underway. Such cells allow for extensive in vitro and in vivo testing as well as "good manufacturing production," reducing the risks in clinical application.
Cell transplantation in Parkinson's disease: problems and perspectives
Curr Opin Neurol. 2010 Aug;23(4):426-32.
Source
Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund, Sweden.
Abstract
Purpose of review: We review recent experiments conducted using embryonic tissue and stem cell transplants in experimental models of Parkinson's disease. We also highlight the challenges which remain to be met in order for cell therapy to become clinically effective and safe.
Recent findings: The outcome of previous clinical transplantation trials was variable in terms of motor recovery. We discuss whether transplants can mitigate L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias and consider the risk factors which predispose to graft-induced dyskinesias. In addition, we introduce Transeuro, a new European Union-funded multicenter consortium which plans to perform transplantation trials.Stem cells have emerged as an alternative source for the generation of dopaminergic precursors. We briefly outline progress made in the use of human embryonic stem cells and focus predominantly on the emerging field of induced pluripotency. We conclude by introducing the exciting and novel method of direct reprogramming which involves the conversion of fibroblasts to neurons without inducing a pluripotent state.
Summary: The area of cell transplantation has been revitalized by the identification of parameters which predispose patients to graft-induced dyskinesias and by the emergence of novel methods of generating dopaminergic neurons. Hopefully, the Transeuro clinical trials will give further impetus and act as a stepping stone to future trials employing stem-cell-derived neurons.
Stem cell replacement therapies for Parkinson's disease
Biochem Biophys Res Commun. 2010 May 21;396(1):152-6.
Source
Laboratory of Molecular Neurobiology, MBB, Center for Developmental Biology and Regenerative Medicine, Scheelevagen 1, 17177 Stockholm, Sweden.
Ernest.Arenas@ki.se
Abstract
Current therapeutic approaches for Parkinson's disease (PD) provide symptomatic relief but none of them change the course of disease. There is therefore a clear need for regenerative and cell replacement therapies (CRT). However, CRT faces several important challenges. First, the main symptoms of PD result from the loss of midbrain dopamine (DA) neurons, but other cell types are also affected. Second, transplantation of human ventral midbrain tissue from aborted fetuses has lead to proof of principle that CRT may work, however, it has also pointed out to important patient-, surgery- and cell preparation-related variables, which need to be improved. Third, while some patients have developed dyskinesias and, with time, Lewy bodies in the grafted cells, other patients have experienced remarkable improvement and have been able to stop their medication. Is there a case for PD CRT today? What is the possible contribution of stem cells to CRT? In this review, I will discuss what we learned from clinical trials using fetal tissue grafts, recent progress in the development of human stem cell-derived-DA neurons for CRT, and some of the issues that need to be solved in order to develop stem cells as tools for PD CRT.
Hematopoietic SCT for the treatment of multiple sclerosis
Bone Marrow Transplant. 2010 Dec;45(12):1671-81.
Source
The Ottawa Hospital Blood and Marrow Transplant Programme, The Ottawa Hospital, 501 Smyth Road, Ottawa, Ontario, Canada.
hatkins@ohri.ca
Abstract
Multiple sclerosis (MS) is the leading autoimmune indication for autologous hematopoietic SCT (aHSCT). Patient selection criteria and transplant interventions have been refined through a series of cohort and registry studies. High- and low-intensity chemotherapy-based conditioning regimens have been used, creating trade-offs between toxicity and effectiveness. TBI has been associated with greater toxicity and poor outcomes. aHSCT stops MS relapses and lessens the disability in malignant MS, which otherwise rapidly incapacitates patients. Better responses occur in progressive MS earlier in the disease when it has a more inflammatory nature. aHSCT prevents further disability in many patients, but some actually recover from their infirmities. Current regimens and supportive care result in very low morbidity and mortality. MS patients experience unique complications in addition to the expected toxicities. Cytokines used alone for stem-cell mobilization may induce MS flares but are safe to be used in combination with steroids or cytotoxic agents. Urinary tract infections, herpes virus reactivation and an engraftment syndrome may occur early after aHSCT. Rarely secondary autoimmune diseases have been reported late after HSCT. Increasing experience in caring for patients with MS has reduced the frequency and severity of toxicity. Conceived as an opportunity to 'reboot' a tolerant immune system, aHSCT is successful in treating patients with MS that is refractory to conventional immunomodulatory drugs.
Clinical outcome of autologous peripheral blood stem cell transplantation in opticospinal and conventional forms of secondary progressive multiple sclerosis in a Chinese population
Ann Hematol. 2011 Mar;90(3):343-8.
Juan Xu, Bing-Xin Ji, Li Su, Hui-Qing Dong, Wan-Ling Sun, Sui-Gui Wan, Ya-Ou Liu, Pu Zhang, Cong-Yan Liu
Source
Department of Hematology, Xuan Wu Hospital, Capital Medical University, No. 45 Changchun Street, Xuan Wu District, Beijing, China.
xujuandail@x263.net
Abstract
To evaluate clinical outcomes of autologous peripheral blood stem cell transplantation (APBCST) between opticospinal multiple sclerosis (OSMS) and conventional multiple sclerosis (CMS) during disease progressive stage in a Chinese population. Thirty-six secondary progressive MS patients, among whom 21 were with OSMS and 15 with CMS, underwent APBSCT and were followed up for an average of 48.92 months (range, 10-91 months). Peripheral blood stem cells were obtained by leukapheresis after mobilization with granulocyte colony-stimulating factor. Modified BEAM conditioning regimen (Tiniposide, melphalan, carmustin, and cytosine arabinoside) were administered. Outcomes were evaluated using the expanded disability status scale (EDSS). No maintenance treatment was administered if there was no disease progression. No treatment-related mortality occurred. Among the 36 patients, one OSMS patient dropped during the follow-up. Among the 22 relapse-free patients, 20 were with continuous neurological improvement without any relapse events, and two remained in neurologically stable states. Among the 13 relapse patients, seven had experienced of neurological relapse, but with no progression during the follow-up period; and six experienced neurological deterioration after transplantation and needed further immunosuppressant treatment. The confirmed relapse-free survival rate was 62.9% and progression-free survival rate was 83.3% after 91 months according to Kaplan and Meier survival curves. Eleven of the 20 OSMS patients (55%) and two of the 15 CMS patients (13.3%) stayed in disease active group (P = 0.014). For the 20 OSMS patients, the overall EDSS score decreased significantly after transplantation (P = 0.016), while visual functions had no significant improvement (P = 0.716). Progressive OSMS has a higher relapse rate than CMS following APBSCT.
The treatment of neurodegenerative disorders using umbilical cord blood and menstrual blood-derived stem cells
Cell Transplant. 2011;20(1):85-94.
Paul R Sanberg, David J Eve, Alison E Willing, Svitlana Garbuzova-Davis, Jun Tan, Cyndy D Sanberg, Julie G Allickson, L Eduardo Cruz, Cesar V Borlongan
Source
Center of Excellence for Aging & Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL 33612, USA.
psanberg@health.usf.edu
Abstract
Stem cell transplantation is a potentially important means of treatment for a number of disorders. Two different stem cell populations of interest are mononuclear umbilical cord blood cells and menstrual blood-derived stem cells. These cells are relatively easy to obtain, appear to be pluripotent, and are immunologically immature. These cells, particularly umbilical cord blood cells, have been studied as either single or multiple injections in a number of animal models of neurodegenerative disorders with some degree of success, including stroke, Alzheimer's disease, amyotrophic lateral sclerosis, and Sanfilippo syndrome type B. Evidence of anti-inflammatory effects and secretion of specific cytokines and growth factors that promote cell survival, rather than cell replacement, have been detected in both transplanted cells.
Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: a pilot study
J Neuroimmunol. 2010 Oct 8;227(1-2):185-9.
Bassem Yamout, Roula Hourani, Haytham Salti, Wissam Barada, Taghrid El-Hajj, Aghiad Al-Kutoubi, Aline Herlopian, Elizabeth Kfoury Baz, Rami Mahfouz, Rima Khalil-Hamdan, Nabeela M A Kreidieh, Marwan El-Sabban, Ali Bazarbachi
Source
Departments of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
yamoutba@idm.net.lb
Abstract
We explore the safety, and therapeutic benefit of intrathecal injection of ex-vivo expanded autologous bone marrow derived mesenchymal stem cells (BM-MSCs) in 10 patients with advanced multiple sclerosis (MS). Patients were assessed at 3, 6 and 12 months. Assessment at 3-6 months revealed Expanded Disability Scale Score (EDSS) improvement in 5/7, stabilization in 1/7, and worsening in 1/7 patients. MRI at 3 months revealed new or enlarging lesions in 5/7 and Gadolinium (Gd+) enhancing lesions in 3/7 patients. Vision and low contrast sensitivity testing at 3 months showed improvement in 5/6 and worsening in 1/6 patients. Early results show hints of clinical but not radiological efficacy and evidence of safety with no serious adverse events.
Stem cells as therapeutics for neurodegenerative disorders
Expert Rev Neurother. 2001 Nov;1(2):267-73.
Source
Laboratory of Neurosciences, National Institute on Aging GRC 4F01, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
mattsonm@grc.nia.nih.gov
Abstract
Aging is associated with a progressive increase in the risk of several prominent neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke and amyotrophic lateral sclerosis. In each of these disorders specific populations of neurons become dysfunctional, then die and are not replaced. The adult brain and spinal cord contain populations of so-called neural stem cells (self-renewing and multipotent) and neural precursor cells (specified to a certain fate, but still mitotic) that may provide a continuing source of new neurons and glial cells during successful aging and after injury to the nervous system. Recent studies have shown that stem cells from embryos and adults can be transplanted into the nervous system, differentiate into neurons and glia and restore lost function in experimental models of neurodegenerative diseases. Embryonic stem cells may be a particularly effective donor cell type for transplantation-based therapies. Efficacy of stem cell therapies remains to be established in clinical trials in humans. Another approach is to mobilize endogenous neural stem cells. Animals studies have shown that dietary and behavioral modifications can indeed stimulate neurogenesis. Molecular and cellular mechanisms that regulate the proliferation, differentiation and survival of neural stem cells and neural precursor cells are being elucidated and are revealing novel targets for the development of pharmaceuticals that promote neurogenesis.
Mesenchymal stem cells for multiple sclerosis: does neural differentiation really matter?
Curr Stem Cell Res Ther. 2011 Mar;6(1):69-72.
Antonio Uccelli, Sara Morando, Silvia Bonanno, Ivan Bonanni, Alessandro Leonardi, Gianluigi Mancardi
Source
Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Italy.
auccelli@neurologia.unige.it
Abstract
The lack of therapies fostering remyelination and regeneration of the neural network deranged by the autoimmune attack occurring in multiple sclerosis (MS), is raising great expectations about stem cells therapies for tissue repair. Mesenchymal stem cells (MSCs) have been proposed as a possible treatment for MS due to the reported capacity of transdifferentiation into neural cells and their ability at modulating immune responses. However, recent studies have demonstrated that many other functional properties are likely to play a role in the therapeutic plasticity of MSCs, including anti-apoptotic, trophic and anti-oxidant effects. These features are mostly based on the paracrine release of soluble molecules, often dictated by local environmental cues. Based on the modest evidence of long-term engraftment and the striking clinical effects that are observed immediately after MSCs administration in the experimental model of MS, we do not favor a major role for transdifferentiation as an important mechanism involved in the therapeutic effect of MSCs.
Inflammatory cytokine induced regulation of superoxide dismutase 3 expression by human mesenchymal stem cells
Stem Cell Rev Rep. 2010 Dec;6(4):548-59.
Source
Multiple Sclerosis and Stem Cell Group, Institute of Clinical Neurosciences, Clinical Sciences North Bristol, University of Bristol, Bristol, UK.
kevin.kemp@bristol.ac.uk
Abstract
Increasing evidence suggests that bone marrow derived-mesenchymal stem cells (MSCs) have neuroprotective properties and a major mechanism of action is through their capacity to secrete a diverse range of potentially neurotrophic or anti-oxidant factors. The recent discovery that MSCs secrete superoxide dismutase 3 (SOD3) may help explain studies in which MSCs have a direct anti-oxidant activity that is conducive to neuroprotection in both in vivo and in vitro. SOD3 attenuates tissue damage and reduces inflammation and may confer neuroprotective effects against nitric oxide-mediated stress to cerebellar neurons; but, its role in relation to central nervous system inflammation and neurodegeneration has not been extensively investigated. Here we have performed a series of experiments showing that SOD3 secretion by human bone marrow-derived MSCs is regulated synergistically by the inflammatory cytokines TNF-alpha and IFN-gamma, rather than through direct exposure to reactive oxygen species. Furthermore, we have shown SOD3 secretion by MSCs is increased by activated microglial cells. We have also shown that MSCs and recombinant SOD are able to increase both neuronal and axonal survival in vitro against nitric oxide or microglial induced damage, with an increased MSC-induced neuroprotective effect evident in the presence of inflammatory cytokines TNF-alpha and IFN-gamma. We have shown MSCs are able to convey these neuroprotective effects through secretion of soluble factors alone and furthermore demonstrated that SOD3 secretion by MSCs is, at least, partially responsible for this phenomenon. SOD3 secretion by MSCs maybe of relevance to treatment strategies for inflammatory disease of the central nervous system.
A consensus statement addressing mesenchymal stem cell transplantation for multiple sclerosis
Stem Cell Rev Rep. 2010 Dec;6(4):500-6.
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.
Mechanisms of oxidative damage in multiple sclerosis and a cell therapy approach to treatment
Autoimmune Dis. 2010 Dec 15;2011:164608.
Source
Multiple Sclerosis and Stem Cell Group, Institute of Clinical Neurosciences, School of Clinical Sciences, University of Bristol, Bristol BS16 1LE, UK.
Abstract
Although significant advances have recently been made in the understanding and treatment of multiple sclerosis, reduction of long-term disability remains a key goal. Evidence suggests that inflammation and oxidative stress within the central nervous system are major causes of ongoing tissue damage in the disease. Invading inflammatory cells, as well as resident central nervous system cells, release a number of reactive oxygen and nitrogen species which cause demyelination and axonal destruction, the pathological hallmarks of multiple sclerosis. Reduction in oxidative damage is an important therapeutic strategy to slow or halt disease processes. Many drugs in clinical practice or currently in trial target this mechanism. Cell-based therapies offer an alternative source of antioxidant capability. Classically thought of as being important for myelin or cell replacement in multiple sclerosis, stem cells may, however, have a more important role as providers of supporting factors or direct attenuators of the disease. In this paper we focus on the antioxidant properties of mesenchymal stem cells and discuss their potential importance as a cell-based therapy for multiple sclerosis.
Why should mesenchymal stem cells (MSCs) cure autoimmune diseases?
Curr Opin Immunol. 2010 Dec;22(6):768-74.
Source
Department of Neurosciences Ophthalmology and Genetics, University of Genoa, Italy.
auccelli@neurologia.unige.it
Abstract
The adult stem/progenitor cells from bone marrow and other tissues referred to as mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) display a significant therapeutic plasticity as reflected by their ability to enhance tissue repair and influence the immune response both in vitro and in vivo. In this review we will focus on the paradigmatic preclinical experience achieved testing MSCs in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. We will emphasize how the paradigm changed over time from the original prediction that MSCs would enhance tissue repair through their transdifferentiation into somatic cells to the current paradigm that they can produce therapeutic benefits without engraftment into the injured tissues. The data will be reviewed in terms of the potentials of MSCs for therapy of autoimmune diseases.
Stem cells in the treatment of stroke
Adv Exp Med Biol. 2010;671:105-16.
Source
University of Michigan, Department of Radiation Oncology, UH B2C490, 1500 E. Medical Center Dr., Ann Arbor, Michigan, USA.
kurbania@med.umich.edu
Abstract
Stroke is an often devastating insult resulting in neurological deficit lasting greater than 24 hours. In the United States, stroke is the third leading cause of death. In those who do not succumb, any outcome from total recovery over a period of weeks to months to persistent profound neurological deficits is possible. Present treatment centers on the decision to administer tissue plasminogen activator, subsequent medical stabilization and early intervention with rehabilitation and risk factor management. The advent of stem cell therapy presents an exciting new frontier for research in stroke treatment, with the potential to cause a paradigm shift from symptomatic control and secondary prevention to reconstitution of neural networks and prevention of neuronal cell death after neurologic injury.
Stem cell transplantation methods
Adv Exp Med Biol. 2010;671:41-57.
Source
UCSD School of Medicine, San Diego, California, USA.
Abstract
Just a few short years ago, we still used to think that we were born with a finite number of irreplaceable neurons. However, in recent years, there has been increasingly persuasive evidence that suggests that neural stem cell (NSC) maintenance and differentiation continue to take ace throughout the mammal's lifetime. Studies suggest that neural stem cells not only persist to mammalian adulthood, but also play a continuous role in brain tissue repair throughout the organism's lifespan. These preliminary results further imply that NSC transplantation strategies might have therapeutic promise in treating neurodegenerative diseases often characterized by isolated or global neuronal and glialloss. The destruction of neural circuitry in neuropathologies such as stroke, Parkinson's disease, MS, SCI prevents signals from being sent throughout the body effectively and is devastating and necessitates a cure. NSC transplantation is among one of the foremost researched fields because it offers promising therapeutic value for regenerative therapy central nervous system (CNS) diseases. Both chemotropic and exogenous cell graft mechanisms ofCNS repair are under review for their therapeutic value and it is hoped that one day, these findings will be applied to human neurodegenerative disorders. The potential applications for NSC transplantations to treat both isolated and global neurodysfunction in humans are innumerable; these prospects include inherited pediatric neurodegenerative and metabolic disorders such as lysosomal storage diseases including leukodystrophies, Sandhoff disease, hypoxic-ischemic encephalopathy and adult CNS disorders characterized by neuronal or glial cell loss such as Parkinson's disease, multiple sclerosis, stroke and spinal cord injury.
The potential of mesenchymal stem cells for neural repair
Discov Med. 2010 Mar;9(46):236-42.
Source
Centers for Stem Cells and Regenerative Medicine, Translational Neuroscience, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
rhm3@case.edu
Abstract
Developing effective therapies for serious neurological insults remains a major challenge for biomedical research. Despite intense efforts, the ability to promote functional recovery after contusion injuries, ischemic insults, or the onset of neurodegenerative diseases in the brain and spinal cord remains very limited even while the need for such therapies is increasing with an aging population. Recent studies suggest that cellular therapies utilizing mesenchymal stem cells (MSCs) may provide a functional benefit in a wide range of neurological insults. MSCs derived from a variety of tissue sources have been therapeutically evaluated in animal models of stroke, spinal cord injury, and multiple sclerosis. In each situation, treatment with MSCs results in substantial functional benefit and these pre-clinical studies have led to the initiation of a number of clinical trials worldwide in neural repair.
Human mesenchymal stem cell transplantation protects against cerebral ischemic injury and upregulates interleukin-10 expression in Macacafascicularis
Brain Res. 2010 Jun 2;1334:65-72.
Jiamei Li, Hua Zhu, Ying Liu, Qin Li, Shan Lu, Ming Feng, Yanfeng Xu, Lan Huang, Chunmei Ma, Yihua An, Robert Chunhua Zhao, Renzhi Wang, Chuan Qin
Source
Institute of Laboratory Animal Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100021, PR China.
Abstract
Mesenchymal stem cell (MSC) transplantation has been reported to improve neurologic function after ischemic injury. However, the detailed mechanisms by which MSCs promote functional recovery are not fully understood. Interleukin-10 (IL-10) is a well-known anti-inflammatory cytokine with neuroprotective effects with respect to brain injury. In this study, a non-human primate ischemia model was used to test the hypothesis that transplanted human bone-marrow-derived MSCs (hBMSCs) exert a neuroprotective effects on cerebral ischemia and upregulate IL-10 expression. We also assessed neuronal apoptosis and astroglial activity in the area around the ischemic lesion and proliferating cells in the subventricular zone (SVZ). Results showed that hBMSC transplantation in ischemic tissues improved the neurological functions and induced an increase in IL-10 expression. In addition, neuronal apoptosis and astroglial activity in the peri-ischemic area decreased, and the number of proliferating cells in the SVZ increased. These results provide a novel therapeutic strategy for improving neurologic function after cerebral ischemia.
Enhancing trophic support of mesenchymal stem cells by ex vivo treatment with trophic factors
J Neurol Sci. 2010 Nov 15;298(1-2):28-34.
Source
Brain Disease Research Center, Department of Neurosurgery, Ajou University School of Medicine, Suwon, Republic of Korea.
Abstract
Background: Several studies have examined the enhanced efficacy of mesenchymal stem cells (MSCs) using neurotrophic factor transfection in ischemic rat models. However, gene therapy, e.g., the application of MSCs transfected with neurotrophic factors, is not feasible in clinical practice for ethical reasons. Therefore, we evaluated cultivation with specific trophic factors in an attempt to enhance the efficacy of human MSCs (hMSCs) in ischemic stroke.
Methods: Using quantitative sandwich enzyme-linked immunosorbent assay (ELISA), we analyzed the levels of trophic factors released from hMSCs after treatment with ischemic brain extract. Trophic factors were pretreated under ex vivo culture conditions. The concentrations of each trophic factor produced by the trophic factor-pretreated and non-pretreated hMSCs were then measured and compared.
Results: hMSCs cultured with ischemic rat brain extract showed increased production of BDNF (brain-derived neurotrophic factor), VEGF (vascular endothelial growth factor) and HGF (hepatocyte growth factor). Ex vivo treatment with trophic factors led to a further increase in the production of the trophic factor by hMSC, suggesting autocrine regulation of hMSCs. The morphology and expression of surface markers of hMSCs were not changed, but the cell viability and cell proliferation ability increased after treatment with trophic factors.
Conclusions: Our data indicate that hMSCs provide trophic support to the ischemic brain, which can be enhanced by ex vivo treatment of trophic factors during cultivation of hMSCs.
Stem cells in human neurodegenerative disorders--time for clinical translation?
J Clin Invest. 2010 Jan;120(1):29-40.
Source
Laboratory of Neurogenesis and Cell Therapy, Wallenberg Neuroscience Center, University Hospital, Lund, Sweden.
olle.lindvall@med.lu.se
Abstract
Stem cell-based approaches have received much hype as potential treatments for neurodegenerative disorders. Indeed, transplantation of stem cells or their derivatives in animal models of neurodegenerative diseases can improve function by replacing the lost neurons and glial cells and by mediating remyelination, trophic actions, and modulation of inflammation. Endogenous neural stem cells are also potential therapeutic targets because they produce neurons and glial cells in response to injury and could be affected by the degenerative process. As we discuss here, however, significant hurdles remain before these findings can be responsibly translated to novel therapies. In particular, we need to better understand the mechanisms of action of stem cells after transplantation and learn how to control stem cell proliferation, survival, migration, and differentiation in the pathological environment.
Stem cell transplantation for ischemic stroke
Cochrane Database Syst Rev. 2010 Sep 8;(9):CD007231.
Source
Department of Neurology, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Via Celoria 11, Milano, Italy, 20133.
Abstract
Background: Studies in animal models of ischemic stroke have shown that stem cells transplanted into the brain can lead to functional improvement. However, to date, evidence for the benefits of stem cell transplantation in ischemic stroke patients is lacking.
Objectives: To assess the efficacy and safety of stem cell transplantation compared with conventional treatments in patients with ischemic stroke.
Search strategy: We searched the Cochrane Stroke Group Trials Register (last searched February 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 3), MEDLINE (1966 to August 2008), EMBASE (1980 to August 2008), Science Citation Index (1900 to August 2008), and BIOSIS (1926 to August 2008). We handsearched potentially relevant conference proceedings, screened reference lists, and searched ongoing trials and research registers (last searched November 2008). We also contacted individuals active in the field and stem cell manufacturers (last contacted December 2008).
Selection criteria: We included randomized controlled trials (RCTs) recruiting patients with ischemic stroke, in any phase of the disease, and an ischemic lesion confirmed by computerized tomography or magnetic resonance imaging scan. We included all types of stem cell transplantation regardless of cell source (autograft, allograft, or xenograft; embryonic, fetal, or adult; from brain or other tissues), route of cell administration (systemic or local), and dosage. The primary outcome was efficacy (assessed as combined functional outcome or disability and dependency) at longer follow-up (minimum six months). Secondary outcomes included post-procedure safety outcomes (death, worsening of neurological deficit, infections and neoplastic transformation).
Data collection and analysis: Two review authors independently extracted data and assessed trial quality. We contacted study authors for additional information.
Main results: We identified three very small RCTs. Two are still awaiting classification because only subgroups of patients could be included in this meta-analysis and additional unpublished data are needed. The third trial randomized 30 patients to intravenous transplantation of autologous mesenchymal stem cell (10 participants) or reference group (20 participants) (five participants, initially randomized to the intervention group, refused the treatment and were allocated to the reference group) and found a statistically non-significant functional improvement in treated patients at longer follow-up. No adverse cell-related events were reported.
Authors' conclusions: No large trials of stem cell transplantation have been performed in ischemic stroke patients and it is too early to know whether this intervention can improve functional outcome. Large, well-designed trials are needed.
Adipose-derived mesenchymal stem cells markedly attenuate brain infarct size and improve neurological function in rats
J Transl Med. 2010 Jun 28;8:63.
Source
Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Abstract
Background: The therapeutic effect of adipose-derived mesenchymal stem cells (ADMSCs) on brain infarction area (BIA) and neurological status in a rat model of acute ischemic stroke (IS) was investigated.
Methods: Adult male Sprague-Dawley (SD) rats (n = 30) were divided into IS plus intra-venous 1 mL saline (at 0, 12 and 24 h after IS induction) (control group) and IS plus intra-venous ADMSCs (2.0 x 106) (treated interval as controls) (treatment group) after occlusion of distal left internal carotid artery. The rats were sacrificed and brain tissues were harvested on day 21 after the procedure.
Results: The results showed that BIA was larger in control group than in treatment group (p < 0.001). The sensorimotor functional test (Corner test) identified a higher frequency of turning movement to left in control group than in treatment group (p < 0.05). mRNA expressions of Bax, caspase 3, interleukin (IL)-18, toll-like receptor-4 and plasminogen activator inhibitor-1 were higher, whereas Bcl-2 and IL-8/Gro were lower in control group than in treatment group (all p < 0.05). Western blot demonstrated a lower CXCR4 and stromal-cell derived factor-1 (SDF-1) in control group than in treatment group (all p < 0.01). Immunohistofluorescent staining showed lower expressions of CXCR4, SDF-1, von Willebran factor and doublecortin, whereas the number of apoptotic nuclei on TUNEL assay was higher in control group than in treatment group (all p < 0.001). Immunohistochemical staining showed that cellular proliferation and number of small vessels were lower but glial fibrillary acid protein was higher in control group than in treatment group (all p < 0.01).
Conclusions: ADMSC therapy significantly limited BIA and improved sensorimotor dysfunction after acute IS.
Comparison of mesenchymal stem cells from adipose tissue and bone marrow for ischemic stroke therapy
Cytotherapy. 2011 Jul;13(6):675-85.
Yuka Ikegame, Kentaro Yamashita, Shin-Ichiro Hayashi, Hiroshi Mizuno, Masahiro Tawada, Fukka You, Kiyofumi Yamada, Yoshitaka Tanaka, Yusuke Egashira, Shigeru Nakashima, Shin-Ichi Yoshimura, Toru Iwama
Source
Department of Neurosurgery, Gifu University Graduate School of Medicine, Gifu, Japan.
ikegame-nsu@umin.ac.jp
Abstract
Background aims: Transplantation of mesenchymal stromal cells (MSC) derived from bone marrow (BM) or adipose tissue is expected to become a cell therapy for stroke. The present study compared the therapeutic potential of adipose-derived stem cells (ASC) with that of BM-derived stem cells (BMSC) in a murine stroke model.
Methods: ASC and BMSC were isolated from age-matched C57BL/6J mice. These MSC were analyzed for growth kinetics and their capacity to secrete trophic factors and differentiate toward neural and vascular cell lineages in vitro. For in vivo study, ASC or BMSC were administrated intravenously into recipient mice (1 × 10(5) cells/mouse) soon after reperfusion following a 90-min middle cerebral artery occlusion. Neurologic deficits, the degree of infarction, expression of factors in the brain, and the fate of the injected cells were observed.
Results: ASC showed higher proliferative activity with greater production of vascular endothelial cell growth factor (VEGF) and hepatocyte growth factor (HGF) than BMSC. Furthermore, in vitro conditions allowed ASC to differentiate into neural, glial and vascular endothelial cells. ASC administration showed remarkable attenuation of ischemic damage, although the ASC were not yet fully incorporated into the infarct area. Nonetheless, the expression of HGF and angiopoietin-1 in ischemic brain tissue was significantly increased in ASC-treated mice compared with the BMSC group.
Conclusions: Compared with BMSC, ASC have great advantages for cell preparation because of easier and safer access to adipose tissue. Taken together, our findings suggest that ASC would be a more preferable source for cell therapy for brain ischemia than BMSC.
A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke
Stem Cells. 2010 Jun;28(6):1099-106.
Jin Soo Lee, Ji Man Hong, Gyeong Joon Moon, Phil Hyu Lee, Young Hwan Ahn, Oh Young Bang; STARTING collaborators
Source
Department of Neurology, Ajou University School of Medicine, Suwon, South Korea.
Abstract
We previously evaluated the short-term follow-up preliminary data of mesenchymal stem cells (MSCs) transplantation in patients with ischemic stroke. The present study was conducted to evaluate the long-term safety and efficacy of i.v. MSCs transplantation in a larger population. To accomplish this, we performed an open-label, observer-blinded clinical trial of 85 patients with severe middle cerebral artery territory infarct. Patients were randomly allocated to one of two groups, those who received i.v. autologous ex vivo cultured MSCs (MSC group) or those who did not (control group), and followed for up to 5 years. Mortality of any cause, long-term side effects, and new-onset comorbidities were monitored. Of the 52 patients who were finally included in this study, 16 were the MSC group and 36 were the control group. Four (25%) patients in the MSC group and 21 (58.3%) in the control group died during the follow-up period, and the cumulative surviving portion at 260 weeks was 0.72 in the MSC group and 0.34 in the control group (log-rank; p = .058). Significant side effects were not observed following MSC treatment. The occurrence of comorbidities including seizures and recurrent vascular episodes did not differ between groups. When compared with the control group, the follow-up modified Rankin Scale (mRS) score was decreased, whereas the number of patients with a mRS of 0-3 increased in the MSC group (p = .046). Clinical improvement in the MSC group was associated with serum levels of stromal cell-derived factor-1 and the degree of involvement of the subventricular region of the lateral ventricle. Intravenous autologous MSCs transplantation was safe for stroke patients during long-term follow-up. This therapy may improve recovery after stroke depending on the specific characteristics of the patients.
Adipose tissue stem cells in peripheral nerve regeneration-In vitro and in vivo
J Neurosci Res. 2021 Feb;99(2):545-560.
Source
Department of Plastic Surgery, Hand Surgery and Burn Center, University Hospital RWTH Aachen, Aachen, Germany.
Abstract
After peripheral nerve injury, Schwann cells (SCs) are crucially involved in several steps of the subsequent regenerative processes, such as the Wallerian degeneration. They promote lysis and phagocytosis of myelin, secrete numbers of neurotrophic factors and cytokines, and recruit macrophages for a biological debridement. However, nerve injuries with a defect size of >1 cm do not show proper tissue regeneration and require a surgical nerve gap reconstruction. To find a sufficient alternative to the current gold standard-the autologous nerve transplant-several cell-based therapies have been developed and were experimentally investigated. One approach aims on the use of adipose tissue stem cells (ASCs). These are multipotent mesenchymal stromal cells that can differentiate into multiple phenotypes along the mesodermal lineage, such as osteoblasts, chondrocytes, and myocytes. Furthermore, ASCs also possess neurotrophic features, that is, they secrete neurotrophic factors like the nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, ciliary neurotrophic factor, glial cell-derived neurotrophic factor, and artemin. They can also differentiate into the so-called Schwann cell-like cells (SCLCs). These cells share features with naturally occurring SCs, as they also promote nerve regeneration in the periphery. This review gives a comprehensive overview of the use of ASCs in peripheral nerve regeneration and peripheral nerve tissue engineering both in vitro and in vivo. While the sustainability of differentiation of ASCs to SCLCs in vivo is still questionable, ASCs used with different nerve conduits, such as hydrogels or silk fibers, have been shown to promote nerve regeneration.
Mesenchymal stem cells in chemotherapy-induced peripheral neuropathy: A new challenging approach that requires further investigations
J Tissue Eng Regen Med. 2020 Jan;14(1):108-122.
Source
Department of Pharmacy and Biotechnology, Faculty of Medicine and Health Sciences, University of Palestine, Gaza, Palestine.
Abstract
Chemotherapeutic drugs may disrupt the nervous system and cause chemotherapy-induced peripheral neuropathy (CIPN) as side effects. There are no completely successful medications for the prevention or treatment of CIPN. Many drugs such as tricyclic antidepressants and anticonvulsants have been used for symptomatic treatment of CIPN. Unfortunately, these drugs often give only partial relief or have dose-limiting side effects. Thus, the treatment of CIPN becomes a challenge because of failure to regenerate and repair the injured neurons. Mesenchymal stem cell (MSC) therapy is a new attractive approach for CIPN. Evidence has demonstrated that MSCs play important roles in reducing oxidative stress, neuroinflammation, and apoptosis, as well as mediating axon regeneration after nerve damage in several experimental studies and some clinical trials. We will briefly review the pathogenesis of CIPN, traditional therapies used and their drawbacks as well as therapeutic effects of MSCs, their related mechanisms, future challenges for their clinical application, and the additional benefit of their combination with pharmacological agents. MSCs-based therapies may provide a new therapeutic strategy for patients suffering from CIPN where further investigations are required for studying their exact mechanisms. Combined therapy with pharmacological agents can provide another promising option for enhancing MSC therapy success while limiting its adverse effects.
Nasal administration of mesenchymal stem cells reverses chemotherapy-induced peripheral neuropathy in mice
Brain Behav Immun. 2021 Mar;93:43-54.
Nabila Boukelmoune, Geoffroy Laumet, Yongfu Tang, Jiacheng Ma, Itee Mahant, Susmita K Singh, Cora Nijboer, Manon Benders, Annemieke Kavelaars, Cobi J Heijnen
Source
Laboratories of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd, Houston, TX 77030, USA.
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequently reported adverse effects of cancer treatment. CIPN often persists long after treatment completion and has detrimental effects on patient's quality of life. There are no efficacious FDA-approved drugs for CIPN. We recently demonstrated that nasal administration of mesenchymal stem cells (MSC) reverses the cognitive deficits induced by cisplatin in mice. Here we show that nasal administration of MSC after cisplatin- or paclitaxel treatment- completely reverses signs of established CIPN, including mechanical allodynia, spontaneous pain, and loss of intraepidermal nerve fibers (IENF) in the paw. The resolution of CIPN is associated with normalization of the cisplatin-induced decrease in mitochondrial bioenergetics in DRG neurons. Nasally administered MSC enter rapidly the meninges of the brain, spinal cord and peripheral lymph nodes to promote IL-10 production by macrophages. MSC-mediated resolution of mechanical allodynia, recovery of IENFs and restoration of DRG mitochondrial function critically depends on IL-10 production. MSC from IL-10 knockout animals are not capable of reversing the symptoms of CIPN. Moreover, WT MSC do not reverse CIPN in mice lacking IL-10 receptors on peripheral sensory neurons. In conclusion, only two nasal administrations of MSC fully reverse CIPN and the associated mitochondrial abnormalities via an IL-10 dependent pathway. Since MSC are already applied clinically, we propose that nasal MSC treatment could become a powerful treatment for the large group of patients suffering from neurotoxicities of cancer treatment.
Structure of neuromuscular junctions and differentiation of striated muscle fibers of mdx mice after bone marrow stem cells therapy
Tsitologiia. 2010;52(5):399-406.
Source
-
Abstract
Mdx mice are a model of Duchenne muscular dystrophy caused by deficiency of dystrophin. Muscles of mdx mice are characterized by high levels of striated muscle fibers death and, accordingly, by a high level of its regeneration. Moreover, the structure of neuromuscular junctions in mdx mice is altered. Changes in the structure of mdx mice neuromuscular junctions against a background of increasing differentiation of striated muscle fibers after C57BL/6 Lin (-) bone marrow stem cells transplantation were investigated. The muscles were studied in 4, 8, 16 and 24 weeks after transplantation. We observed that the level of striated muscle fibers loss was decreased from the 4th week after transplantation of bone marrow stem cells. Accumulation of muscle fibers without centrally located nuclei began from the 8th week, and dystrophin synthesis was increased at the 16th and 24th weeks after bone marrow stem cells transplantation. Longitudinal sections of quadriceps muscles of mdx mice showed decrease in the number of acetylcholine receptors clusters in neuromuscular junctions and a simultaneous increase in acetylcholine receptor clusters area during the 4th week after transplantation. In 16 weeks after bone marrow stem cells transplantation, total neuromuscular junction area was increased due to increase in the area of acetylcholine receptors clusters and to increase in their number as well. Thus, single intramuscular transplantation of C57BL/6 Lin (-) bone marrow stem cells induces an increase in differentiation of mdx mice striated muscle fibers and improves the structure of neuromuscular junctions.
Co-administration of ibuprofen and nitric oxide is an effective experimental therapy for muscular dystrophy, with immediate applicability to humans
Br J Pharmacol. 2010 Jul;160(6):1550-60.
Clara Sciorati, Roberta Buono, Emanuele Azzoni, Silvana Casati, Pierangela Ciuffreda, Grazia D'Angelo, Dario Cattaneo, Silvia Brunelli, Emilio Clementi
Source
San Raffaele Scientific Institute, Stem Cell Research Institute, Milan, Italy.
Abstract
Background and purpose: Current therapies for muscular dystrophy are based on corticosteroids. Significant side effects associated with these therapies have prompted several studies aimed at identifying possible alternative strategies. As inflammation and defects of nitric oxide (NO) generation are key pathogenic events in muscular dystrophies, we have studied the effects of combining the NO donor isosorbide dinitrate (ISDN) and the non-steroidal anti-inflammatory drug ibuprofen.
Experimental approach: alpha-Sarcoglycan-null mice were treated for up to 8 months with ISDN (30 mg.kg(-1)) plus ibuprofen (50 mg.kg(-1)) administered daily in the diet. Effects of ISDN and ibuprofen alone were assessed in parallel. Drug effects on animal motility and muscle function, muscle damage, inflammatory infiltrates and cytokine levels, as well as muscle regeneration including assessment of endogenous stem cell pool, were measured at selected time points.
Key results: Combination of ibuprofen and ISDN stimulated regeneration capacity, of myogenic precursor cells, reduced muscle necrotic damage and inflammation. Muscle function in terms of free voluntary movement and resistance to exercise was maintained throughout the time window analysed. The effects of ISDN and ibuprofen administered separately were transient and significantly lower than those induced by their combination.
Conclusions and implications: Co-administration of NO and ibuprofen provided synergistic beneficial effects in a mouse model of muscular dystrophy, leading to an effective therapy. Our results open the possibility of immediate clinical testing of a combination of ISDN and ibuprofen in dystrophic patients, as both components are approved for use in humans, with a good safety profile.
Flt-1 haploinsufficiency ameliorates muscular dystrophy phenotype by developmentally increased vasculature in mdx mice
Hum Mol Genet. 2010 Nov 1;19(21):4145-59.
Mayank Verma, Yoko Asakura, Hiroyuki Hirai, Shuichi Watanabe, Christopher Tastad, Guo-Hua Fong, Masatsugu Ema, Jarrod A Call, Dawn A Lowe, Atsushi Asakura
Source
Stem Cell Institute, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Abstract
Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disease caused by mutations in the gene coding for the protein dystrophin. Recent work demonstrates that dystrophin is also found in the vasculature and its absence results in vascular deficiency and abnormal blood flow. This induces a state of ischemia further aggravating the muscular dystrophy pathogenesis. For an effective form of therapy of DMD, both the muscle and the vasculature need to be addressed. To reveal the developmental relationship between muscular dystrophy and vasculature, mdx mice, an animal model for DMD, were crossed with Flt-1 gene knockout mice to create a model with increased vasculature. Flt-1 is a decoy receptor for vascular endothelial growth factor, and therefore both homozygous (Flt-1(-/-)) and heterozygous (Flt-1(+/-)) Flt-1 gene knockout mice display increased endothelial cell proliferation and vascular density during embryogenesis. Here, we show that Flt-1(+/-) and mdx:Flt-1(+/-) adult mice also display a developmentally increased vascular density in skeletal muscle compared with the wild-type and mdx mice, respectively. The mdx:Flt-1(+/-) mice show improved muscle histology compared with the mdx mice with decreased fibrosis, calcification and membrane permeability. Functionally, the mdx:Flt-1(+/-) mice have an increase in muscle blood flow and force production, compared with the mdx mice. Consequently, the mdx:utrophin(-/-):Flt-1(+/-) mice display improved muscle histology and significantly higher survival rates compared with the mdx:utrophin(-/-) mice, which show more severe muscle phenotypes than the mdx mice. These data suggest that increasing the vasculature in DMD may ameliorate the histological and functional phenotypes associated with this disease.
Stem cell therapies to treat muscular dystrophy: progress to date
BioDrugs. 2010 Aug 1;24(4):237-47.
Source
Stem Cell Laboratory, Dipartimento di Scienze Neurologiche, Centro Dino Ferrari, Università di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
Abstract
Muscular dystrophies are heritable, heterogeneous neuromuscular disorders and include Duchenne and Becker muscular dystrophies (DMD and BMD, respectively). DMD patients exhibit progressive muscle weakness and atrophy followed by exhaustion of muscular regenerative capacity, fibrosis, and eventually disruption of the muscle tissue architecture. In-frame mutations in the dystrophin gene lead to expression of a partially functional protein, resulting in the milder BMD. No effective therapies are available at present. Cell-based therapies have been attempted in an effort to promote muscle regeneration, with the hope that the host cells would repopulate the muscle and improve muscle function and pathology. Injection of adult myoblasts has led to the development of new muscle fibers, but several limitations have been identified, such as poor cell survival and limited migratory ability. As an alternative to myoblasts, stem cells were considered preferable for therapeutic applications because of their capacity for self-renewal and differentiation potential. In recent years, encouraging results have been obtained with adult stem cells to treat human diseases such as leukemia, Parkinson's disease, stroke, and muscular dystrophies. Embryonic stem cells (ESCs) can be derived from mammalian embryos in the blastocyst stage, and because they can differentiate into a wide range of specialized cells, they hold potential for use in treating almost all human diseases. Several ongoing studies focus on this possibility, evaluating differentiation of specific cell lines from human ESCs (hESCs) as well as the potential tumorigenicity of hESCs. The most important limitation with using hESCs is that it requires destruction of human blastocysts or embryos. Conversely, adult stem cells have been identified in various tissues, where they serve to maintain, generate, and replace terminally differentiated cells within their specific tissue as the need arises for cell turnover or from tissue injury. Moreover, these cells can participate in regeneration of more than just their specific tissue type. Here we describe multiple types of muscle- and fetal-derived myogenic stem cells, their characterization, and their possible use in treating muscular dystrophies such as DMD and BMD. We also emphasize that the most promising possibility for the management and therapy of DMD and BMD is a combination of different approaches, such as gene and stem cell therapy.
Targeting fibrosis in Duchenne muscular dystrophy
J Neuropathol Exp Neurol. 2010 Aug;69(8):771-6.
Source
From the Department of Neurology, Neurological Institute, and Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
zhoul2@ccf.org
Abstract
Duchenne muscular dystrophy (DMD) is the most common genetic muscle disease affecting 1 in 3,500 live male births. It is an X-linked recessive disease caused by a defective dystrophin gene. The disease is characterized by progressive limb weakness, respiratory and cardiac failure, and premature death. Fibrosis is a prominent pathological feature of muscle biopsies from patients with DMD. It directly causes muscle dysfunction and contributes to the lethal DMD phenotype. Although gene therapy and cell therapy may ultimately provide a cure for DMD, currently the disease is devastating, with no effective therapies. Recent studies have demonstrated that ameliorating muscle fibrosis may represent a viable therapeutic approach for DMD. By reducing scar formation, antifibrotic therapies may not only improve muscle function but also enhance muscle regeneration and promote gene and stem cell engraftment. Antifibrotic therapy may serve as a necessary addition to gene and cell therapies to treat DMD in the future. Therefore, understanding cellular and molecular mechanisms underlying muscle fibrogenesis associated with dystrophin deficiency is key to the development of effective antifibrotic therapies for DMD.
Stem cell therapies to treat muscular dystrophy: progress to date
BioDrugs. 2010 Aug 1;24(4):237-47.
Source
Stem Cell Laboratory, Dipartimento di Scienze Neurologiche, Centro Dino Ferrari, Università di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
Abstract
Muscular dystrophies are heritable, heterogeneous neuromuscular disorders and include Duchenne and Becker muscular dystrophies (DMD and BMD, respectively). DMD patients exhibit progressive muscle weakness and atrophy followed by exhaustion of muscular regenerative capacity, fibrosis, and eventually disruption of the muscle tissue architecture. In-frame mutations in the dystrophin gene lead to expression of a partially functional protein, resulting in the milder BMD. No effective therapies are available at present. Cell-based therapies have been attempted in an effort to promote muscle regeneration, with the hope that the host cells would repopulate the muscle and improve muscle function and pathology. Injection of adult myoblasts has led to the development of new muscle fibers, but several limitations have been identified, such as poor cell survival and limited migratory ability. As an alternative to myoblasts, stem cells were considered preferable for therapeutic applications because of their capacity for self-renewal and differentiation potential. In recent years, encouraging results have been obtained with adult stem cells to treat human diseases such as leukemia, Parkinson's disease, stroke, and muscular dystrophies. Embryonic stem cells (ESCs) can be derived from mammalian embryos in the blastocyst stage, and because they can differentiate into a wide range of specialized cells, they hold potential for use in treating almost all human diseases. Several ongoing studies focus on this possibility, evaluating differentiation of specific cell lines from human ESCs (hESCs) as well as the potential tumorigenicity of hESCs. The most important limitation with using hESCs is that it requires destruction of human blastocysts or embryos. Conversely, adult stem cells have been identified in various tissues, where they serve to maintain, generate, and replace terminally differentiated cells within their specific tissue as the need arises for cell turnover or from tissue injury. Moreover, these cells can participate in regeneration of more than just their specific tissue type. Here we describe multiple types of muscle- and fetal-derived myogenic stem cells, their characterization, and their possible use in treating muscular dystrophies such as DMD and BMD. We also emphasize that the most promising possibility for the management and therapy of DMD and BMD is a combination of different approaches, such as gene and stem cell therapy.
Splice modification to restore functional dystrophin synthesis in Duchenne muscular dystrophy
Curr Pharm Des. 2010;16(8):988-1001.
Source
Centre for Neuromuscular and Neurological Disorders, University of Western Australia, 4th Floor A Block, QE II Medical Centre, Nedlands, Western Australia, Australia.
swilton@meddent.uwa.edu.au
Abstract
In little more than a decade, induced exon skipping as a therapy to treat Duchenne muscular dystrophy (DMD) has progressed from a concept tested in vitro, to pre-clinical evaluation in mouse and dog models, and recent completion of Phase I clinical trials in man. There is no longer any doubt that antisense oligomers can redirect dystrophin gene processing and by-pass protein truncating mutations after direct injection into muscle. Proof-of-concept has been demonstrated in human dystrophic muscle, with trials in Leiden and London showing that two different oligomer chemistries can restore the reading-frame in selected DMD patients by excising dystrophin exon 51. Systemic delivery of both oligomer types into DMD patients has commenced with promising results but it remains to be established if this therapy will have measurable clinical benefits. Targeted removal of exon 51 will only be directly applicable to about one in ten DMD individuals, and the immediate challenges include development of appropriate and effective delivery regimens, and extending splice-switching therapies to other dystrophin gene lesions. The success of induced exon skipping has spawned a number of "fusion therapies", including vector-mediated dystrophin exon skipping and ex vivo viral delivery of splice-switching antisense molecules into myogenic stem cells, followed by implantation, which may address long term oligomer delivery issues. This review summarizes the pivotal events leading to the completion of the first proof-of-concept trials and speculates on some of the scientific, ethical, regulatory and commercial challenges facing targeted exon skipping for the treatment of DMD.
Microdystrophin delivery in dystrophin-deficient (mdx) mice by genetically-corrected syngeneic MSCs transplantation
Transplant Proc. 2010 Sep;42(7):2731-9.
Source
Department of Medical Genetics, Southern Medical University, Guangzhou, PR China.
Abstract
Cell transplantation and gene therapy are two promising therapeutical approaches for the treatment on Duchenne Muscular Dystrophy (DMD). However, both strategies have met many hurdles, mainly because of the absence of an efficient systemic delivery system on gene therapy and immune reactionns on cell transplantation. In this project, we investigated the strategy based on combination of these two basic ones, ie, transplantation of transgene-corrected mdx mesenchymal stem cells (MSCs) into mdx mice to cure DMD. The MSCs isolated from male mdx mice were transduced with recombinant adenovirus including human microdystrophin gene and labeled with BrdU were transplanted into female mdx mice, the Chimerism with the sex-determinant Y chromosome and human microdystrophin expression were detected. Simultaneously, the plasma creatine kinase (CK) activity, the improvement with the muscles' pathology and contractile propertie were evaluated. The results clearly demonstrated that some human dystrophin and BrdU expression collectively were detected in some muscles of transplanted mdx mice. Moreover, the CK activity and percentage of centrally nucleated fiber (CNF) decreased slightly after transplanation. Regrettably, the protective effect on contraction-induced injury in TA and diaphragm muscles wasn't significantly improvement after transplantation. Our results suggested, if enhancement on the efficiency with cell transplantation, that the transplantation of autologous MSCs corrected by dystrophin may be a form to treat DMD patients in future.
Stem cells to treat muscular dystrophies - where are we?
Neuromuscul Disord. 2011 Jan;21(1):4-12.
Source
The Dubowitz Neuromuscular Centre, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom.
Abstract
The muscular dystrophies are inherited disorders characterised by progressive muscle wasting and weakness. Stem cell therapy is considered to be one of the most promising strategies for treating muscular dystrophies. In this review, we first examine the evidence that a stem cell could be used to treat muscular dystrophies, and then discuss the criteria that an ideal stem cell should meet. We also highlight the importance of standard operation procedures to be followed for ensuring the consistent and reproducible efficacy of a particular stem cell. While at the moment the scientific community is looking for an ideal stem cell to treat muscular dystrophies, it is clear that in order for this field to benefit from therapeutic stem cell applications, additional careful investigations are required.
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