Stemcell Research & Evidence - Lung Conditions
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Mesenchymal stem cell therapy for the treatment of chronic obstructive pulmonary disease
Expert Opin Biol Ther. 2010 May;10(5):681-7.
Source
Department of Experimental Medicine, Second University of Naples, Section of Pharmacology L Donatelli, via S Maria di Costantinopoli, 16-80138 Napoli, Italy.
bruno.dagostino@unina2.it
Abstract
Recent studies have revealed that adult stem cells such as bone marrow-derived cells contribute to lung tissue regeneration and protection, and thus administration of exogenous stem/progenitor cells may be a potent next-generation therapy for COPD. Pathogenesis of COPD is characterized by an upregulation of inflammatory processes leading to irreversible events such as apoptosis of epithelial cells, proteolysis of the terminal air-space and lung extracellular matrix components. The available pharmacological treatments are essentially symptomatic, therefore, there is a need to develop more effective therapeutic strategies. It has been previously demonstrated that transplanted MSC home to the lung in response to lung injury and adopt phenotypes of alveolar epithelial cells, endothelial cells, fibroblasts and bronchial epithelial cells. However, engraftment and differentiation are now felt to be rare occurrences and other mechanisms might be involved and play a more important role. Importantly, MSCs protect lung tissue through suppression of proinflammatory cytokines, and through triggering production of reparative growth factors. Accordingly, it is not clear if and how these cells will be able to repair, to slow or to prevent the disease. This article reviews recent advances in regenerative medicine in COPD and highlights that their potential application although promising and very attractive, are still a far away opinion.
Cell based therapy for COPD
Nihon Rinsho. 2007 Apr;65(4):740-7.
Source
Department of Geriatrics and Gerontology, Tohoku University Hospital.
Abstract
To develop a new cell based therapy for chronic obstructive pulmonary disease (COPD), we need to understand 1) the role of tissue-specific and bone marrow-derived stem cells, 2) extracellular matrix, and 3) growth factors. Recently, bronchioalveolar stem cells were identified in murine distal lungs. Impairment of these stem cells may cause improper lung repair after inflammation, resulting in pulmonary emphysema. Bone marrow-derived cells are necessary to repair injured lungs. However, the long term role of these cells is not understood yet. Although we need more careful analysis and additional experiments, growth factors, such as hepatocyte growth factor, are good candidates for the new cell based therapy for COPD. Lung was believed as a non-regenerative organ. Based on these recent reports about lung regeneration and stem cells, however, new strategies to treat COPD and a new point of view to understand the pathophysiology of COPD are rising.
Stem cell therapy: the great promise in lung disease
Ther Adv Respir Dis. 2008 Jun;2(3):173-7.
Source
Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, via S. Maria di Costantinopoli, 16-80138 Napoli, Italy.
dariosin@uab.edu
Abstract
Lung injuries are leading causes of morbidity and mortality worldwide. Pulmonary diseases such as asthma or chronic obstructive pulmonary disease characterized by loss of lung elasticity, small airway tethers, and luminal obstruction with inflammatory mucoid secretions, or idiopathic pulmonary fibrosis characterized by excessive matrix deposition and destruction of the normal lung architecture, have essentially symptomatic treatments and their management is costly to the health care system.Regeneration of tissue by stem cells from endogenous, exogenous, and even genetically modified cells is a promising novel therapy. The use of adult stem cells to help with lung regeneration and repair could be a newer technology in clinical and regenerative medicine. In fact, different studies have shown that bone marrow progenitor cells contribute to repair and remodeling of lung in animal models of progressive pulmonary hypertension.Therefore, lung stem cell biology may provide novel approaches to therapy and could represent a great promise for the future of molecular medicine. In fact, several diseases can be slowed or even blocked by stem cell transplantation.
Mechanisms of cellular therapy in respiratory diseases
Intensive Care Med. 2011 Sep;37(9):1421-31.
Source
Laboratório de Investigação Pulmonar, Centro de Ciências da Saúde, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho, s/n, Bloco G-014, Ilha do Fundão, Rio de Janeiro, RJ 21941-902, Brazil.
Abstract
Purpose: Stem cells present a variety of clinical implications in the lungs. According to their origin, these cells can be divided into embryonic and adult stem cells; however, due to the important ethical and safety limitations that are involved in the embryonic stem cell use, most studies have chosen to focus on adult stem cell therapy. This article aims to present and clarify the recent advances in the field of stem cell biology, as well as to highlight the effects of mesenchymal stem cell (MSC) therapy in the context of acute lung injury/acute respiratory distress syndrome and chronic disorders such as lung fibrosis and chronic obstructive pulmonary disease.
Methods: For this purpose, we performed a critical review of adult stem cell therapies, covering the main clinical and experimental studies published in Pubmed databases in the past 11 years. Different characteristics were extracted from these articles, such as: the experimental model, strain, cellular type and administration route used as well as the positive or negative effects obtained.
Results: There is evidence for beneficial effects of MSC on lung development, repair, and remodeling. The engraftment in the injured lung does not occur easily, but several studies report that paracrine factors can be effective in reducing inflammation and promoting tissue repair. MSC releases several growth factors and anti-inflammatory cytokines that regulate endothelial and epithelial permeability and reduce the severity of inflammation.
Conclusion: A better understanding of the mechanisms that control cell division and differentiation, as well as of their paracrine effects, is required to enable the optimal use of bone marrow-derived stem cell therapy to treat human respiratory diseases.
Protective role of mesenchymal stem cells and mesenchymal stem cell-derived exosomes in cigarette smoke-induced mitochondrial dysfunction in mice
Toxicol Appl Pharmacol. 2019 Dec 15;385:114788.
Source
Department of Environmental Medicine, University of Rochester Medical Center, Box 850, 601 Elmwood Avenue, Rochester, NY, USA.
Abstract
Background: Cigarette smoke (CS)-induced lung inflammation and Chronic Obstructive Pulmonary disease (COPD) involves mitochondrial dysfunction. Mesenchymal stem cells (MSC) and MSC-derived exosomes (EXO) are reported to show therapeutic effects in many animal models of inflammation and injury. In the present study, we determined the role of MSC and EXO intervention in CS-induced lung inflammation with a focus on mitochondrial dysfunction.
Methods: EXO were characterized using Western blot for exosomal markers, tunable resistive pulse sensing by qNano and transmission electron microscopy (TEM). Mitochondrial reporter mice (mt-Keima and mito-QC) were exposed to air or CS for 10 days. mt-Keima mice were treated with intraperitoneal injections of MSC or EXO or MSC and EXO (MSC + EXO) for 10 days. Total cell counts, differential cell counts were performed using automated cell counter and flow cytometry respectively. Further, the levels of pro-inflammatory mediators in bronchoalveolar lavage (BAL) fluid were measured using ELISA. Western blot analysis, quantitative PCR, confocal microscopy were used in the current study to determine the effects in the lungs of CS exposed mice. Seahorse flux analyzer was used to measure the oxidative-phosphorylation (OXPHOS) in the BEAS2B cells and BEAS2B - mMSC co-culture experiments.
Results: CS exposure increased the inflammatory cellular infiltrations in the lungs of the mt-Keima mice. MSC + EXO treatment showed protection compared to individual treatments (MSC or EXO alone). There were no changes in the mitophagy proteins like PINK1 and Parkin, which was also found using the mito-QC mice. CS exposure led to significant increase in the mitochondrial fission protein DRP1 and other DAMPs pathway mediators like S100A4 and S100A8, HMGB1, RAGE and AGE. MSC + EXO treatment increased the gene expression of (fusion genes) mfn1, mfn2 and opa1. Additionally, the rhot1 gene expression was increased in MSC + EXO treatment group compared to Air- and CS exposed groups. BEAS2B-mMSC co-cultures showed protective response against the CSE-altered mitochondrial respiration parameters, confirming the beneficial effect of MSC towards human bronchial lung epithelial cells.
Conclusion: CS affects some of early mitochondrial genes involved in the fission/fusion process, enhancing the damage response along with altered cytokine levels. MSC + EXO combination treatment showed their protective effects. MSC + EXO combination treatment may act against these early events caused by CS exposure owing to its anti-inflammatory and other mitochondrial transfer mechanisms.
Chronic obstructive pulmonary disease and asthma: mesenchymal stem cells and their extracellular vesicles as potential therapeutic tools
Stem Cell Res Ther. 2022 Jun 20;13(1):262.
Hossein Abbaszadeh, Farzaneh Ghorbani, Sanaz Abbaspour-Aghdam, Amin Kamrani, Hamed Valizadeh, Mehdi Nadiri, Armin Sadeghi, Karim Shamsasenjan, Farhad Jadidi-Niaragh, Leila Roshangar, Majid Ahmadi
Source
Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Abstract
Chronic lung diseases, such as chronic obstructive pulmonary disease (COPD) and asthma, are one of the most frequent causes of morbidity and mortality in the global. COPD is characterized by progressive loss of lung function through inflammation, apoptosis, and oxidative stress caused by chronic exposure to harmful environmental pollutants. Airway inflammation and epithelial remodeling are also two main characteristics of asthma. In spite of extensive efforts from researchers, there is still a great need for novel therapeutic approaches for treatment of these conditions. Accumulating evidence suggests the potential role of mesenchymal stem cells (MSCs) in treatment of many lung injuries due to their beneficial features including immunomodulation and tissue regeneration. Besides, the therapeutic advantages of MSCs are chiefly related to their paracrine functions such as releasing extracellular vesicles (EVs). EVs comprising exosomes and microvesicles are heterogeneous bilayer membrane structures loaded with various lipids, nucleic acids and proteins. Due to their lower immunogenicity, tumorigenicity, and easier management, EVs have appeared as favorable alternatives to stem cell therapies. Therefore, in this review, we provided an overview on the current understanding of the importance of MSCs and MSC-derived EVs from different sources reported in preclinical and clinical COPD and asthmatic models.
The potential of mesenchymal stem cell therapy for chronic lung disease
Expert Rev Respir Med. 2020 Jan;14(1):31-39.
Source
Laboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Abstract
Introduction: Mesenchymal stem/stromal cells (MSCs) have been shown to improve lung function and survival in chronic inflammatory lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), and silicosis.
Areas covered: This review covers rationale for the use of MSC therapy, along with preclinical studies and clinical trials with MSC therapy in chronic lung diseases.
Expert opinion: MSC therapy holds promise for the treatment of chronic lung diseases, mainly when administered at early stages. In clinical trials, MSC administration was safe, but associated with limited effects on clinical outcomes. Further studies are required to elucidate unresolved issues, including optimal MSC source and dose, route of administration, and frequency (single vs. multiple-dose regimens). A better understanding of the mechanisms of MSC action, local microenvironment of each disease, and development of strategies to potentiate the beneficial effects of MSCs may improve outcomes.
Reduction of Emphysema Severity by Human Umbilical Cord-Derived Mesenchymal Stem Cells in Mice
Int J Mol Sci. 2022 Aug 10;23(16):8906.
Vincent Laiman, Yueh-Lun Lee, Yu-Wei Hou, Yu-Ting Fang, You-Yin Chen, Yu-Chun Lo, Didik Setyo Heriyanto, Shu-Chi Lan, Chia-Ling Chen, Xiao-Yue Chen, Kang-Yun Lee, Jer-Hwa Chang, Hsiao-Chi Chuang
Source
International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
Abstract
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality in chronic lung disease patients throughout the world. Mesenchymal stem cells (MSCs) have been shown to regulate immunomodulatory, anti-inflammatory, and regenerative responses. However, the effects of human-umbilical-cord-derived mesenchymal stem cells (hUC-MSCs) on the lung pathophysiology of COPD remain unclear. We aimed to investigate the role of hUC-MSCs in emphysema severity and Yes-associated protein (Yap) phosphorylation (p-Yap) in a porcine-pancreatic-elastase (PPE)-induced emphysema model. We observed that the emphysema percentages (normalized to the total lung volume) measured by chest computed tomography (CT) and exercise oxygen desaturation were significantly reduced by hUC-MSCs at 107 cells/kg body weight (BW) via intravenous administration in emphysematous mice (p < 0.05). Consistently, the emphysema index, as assessed by the mean linear intercept (MLI), significantly decreased with hUC-MSC administration at 3 × 106 and 107 cells/kg BW (p < 0.05). Changes in the lymphocytes, monocytes, and splenic cluster of differentiation 4-positive (CD4+) lymphocytes by PPE were significantly reversed by hUC-MSC administration in emphysematous mice (p < 0.05). An increasing neutrophil/lymphocyte ratio was reduced by hUC-MSCs at 3 × 106 and 107 cells/kg BW (p < 0.05). The higher levels of tumor necrosis factor (TNF)-α, keratinocyte chemoattractant (KC), and lactate dehydrogenase (LDH) in bronchoalveolar lavage fluid (BALF) were significantly decreased by hUC-MSC administration (p < 0.05). A decreasing p-Yap/Yap ratio in type II alveolar epithelial cells (AECII) of mice with PPE-induced emphysema was significantly increased by hUC-MSCs (p < 0.05). In conclusion, the administration of hUC-MSCs improved multiple pathophysiological features of mice with PPE-induced emphysema. The effectiveness of the treatment of pulmonary emphysema with hUC-MSCs provides an essential and significant foundation for future clinical studies of MSCs in COPD patients.
Adipose-derived mesenchymal stem cells protects renal function in a rat model of emphysema
Tissue Cell. 2021 Dec;73:101613.
Source
Department of Physiology, Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. Electronic address:
khoseinynejad@yahoo.com.
Abstract
Background and objective: The link between lung disease and kidney disorders has already been confirmed. Previous studies have documented that obstructive pulmonary disease is an independent predictor of decreased renal function, which reduces glomerular filtration rate. Recently, mesenchymal stem cells are the most important cell used in cell therapy. Accordingly, the present experiment was designed to evaluate the efficacy of adipose-derived mesenchymal stem cells (AMSCs) on improvement of renal function in elastase induced-pulmonary emphysema rats.
Materials and methods: Thirty male Sprague-Dawley rats divided into the 3 groups. Following intra-tracheal administration of elastase, the in vivo emphysema model established and confirmed according to the specific markers. Subsequently, systemic AMSCs injection was developed. the kidney injuries markers such as Blood urea nitrogen (BUN), creatinine, sodium and potassium as well as the kidney histopathologic parameters were assessed in all groups. Moreover, the oxidative stress markers levels including Malondialdehyde (MDA), Total antioxidant capacity (TAC), Catalase (CAT) and Glutathione peroxidase (GPx) were measured in kidney tissue and also inflammatory cytokines including IL-10, IL-6, and IFN-Ƴ were assessed in serum samples.
Results: The marked rise in kidney injuries markers were observed which showed by enhancement of BUN and Creatinine levels in emphysema rats compared to the control. Furthermore, the results demonstrated increases in MDA levels and decreases in antioxidant activity which was in line with increases in inflammation cytokines in renal tissue. Conversely, AMSCs treatment improved renal function as shown by the decreases BUN, Creatinine and proteinuria. Furthermore, renal histological assay demonstrate improvement in glomerular and tubular damage and inflammatory cells accumulation.
Conclusions: Our results documented the promising kidney-protective properties of Adipose-Derived Mesenchymal Stem Cells in the kidney injuries induced by emphysema.
Chronic obstructive pulmonary disease and asthma: mesenchymal stem cells and their extracellular vesicles as potential therapeutic tools
Stem Cell Res Ther. 2022 Jun 20;13(1):262.
Hossein Abbaszadeh, Farzaneh Ghorbani, Sanaz Abbaspour-Aghdam, Amin Kamrani, Hamed Valizadeh, Mehdi Nadiri, Armin Sadeghi, Karim Shamsasenjan, Farhad Jadidi-Niaragh, Leila Roshangar, Majid Ahmadi
Source
Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Abstract
Chronic lung diseases, such as chronic obstructive pulmonary disease (COPD) and asthma, are one of the most frequent causes of morbidity and mortality in the global. COPD is characterized by progressive loss of lung function through inflammation, apoptosis, and oxidative stress caused by chronic exposure to harmful environmental pollutants. Airway inflammation and epithelial remodeling are also two main characteristics of asthma. In spite of extensive efforts from researchers, there is still a great need for novel therapeutic approaches for treatment of these conditions. Accumulating evidence suggests the potential role of mesenchymal stem cells (MSCs) in treatment of many lung injuries due to their beneficial features including immunomodulation and tissue regeneration. Besides, the therapeutic advantages of MSCs are chiefly related to their paracrine functions such as releasing extracellular vesicles (EVs). EVs comprising exosomes and microvesicles are heterogeneous bilayer membrane structures loaded with various lipids, nucleic acids and proteins. Due to their lower immunogenicity, tumorigenicity, and easier management, EVs have appeared as favorable alternatives to stem cell therapies. Therefore, in this review, we provided an overview on the current understanding of the importance of MSCs and MSC-derived EVs from different sources reported in preclinical and clinical COPD and asthmatic models.
Human Umbilical Cord-Derived Mesenchymal Stem Cells Repair SU5416-Injured Emphysema
Int J Stem Cells. 2022 Nov 30;15(4):395-404.
Source
Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China.
Abstract
Background and objectives: Chronic obstructive pulmonary disease (COPD) is a common, frequently-occurring disease and poses a major health concern. Unfortunately, there is current no effective treatment for COPD, particularly emphysema. Recently, experimental treatment of COPD using mesenchymal stem cells (MSCs) mainly focused on bone marrow-derived MSCs (BM-MSCs). Human umbilical cord-derived MSCs (hUC-MSCs) have more advantages compared to BM-MSCs. However, studies on the role of hUC-MSCs in management of COPD are limited. This study sought to explore the role of hUC-MSCs and its action mechanisms in a rat model of VEGF receptor blocker SU5416-injured emphysema.
Methods and results: hUC-MSCs were characterized by immunophenotype and differentiation analysis. Rats were divided into four groups: Control, Control＋MSC, SU5416 and SU5416＋MSC. Rats in model group were administered with SU5416 for three weeks. At the end of the second week after SU5416 administration, model group were infused with 3×106 hUC-MSCs through tail vein. After 14 days from hUC-MSCs transplantation, rats were euthanized and data were analyzed. HE staining and mean linear intercepts showed that SU5416-treated rats exhibited typical emphysema while emphysematous changes in model rats after hUC-MSCs transplantation disappeared completely and were restored to normal phenotype. Furthermore, hUC-MSCs inhibited apoptosis as shown by TUNEL and Western blotting. ELISA and Western blotting showed hUC-MSCs rescued VEGF-VEGFR2-AKT pathway in emphysematous lungs.
Conclusions: The findings show that hUC-MSCs effectively repair the emphysema injury. This study provides the first evidence that hUC-MSCs inhibit apoptosis via rescuing VEGF- VEGFR2-AKT pathway in a rat model of emphysema.
Deriving respiratory cell types from stem cells
Curr Stem Cell Res Ther. 2007 Sep;2(3):197-208.
Source
Department of Physiology, Monash University, Clayton, 3800, Australia.
Abstract
The reported pluripotential capabilities of many human stem cell types has made them an attractive area of research, given the belief they may hold considerable therapeutic potential for treating a wide range of human diseases and injuries. Although the bulk of stem cell based research has focused on developing procedures for the treatment of pancreatic, neural, cardiovascular and haematopoietic diseases, the potential for deriving respiratory cell types from stem cells for treatment of respiratory specific diseases has also been explored. It is suggested that stem cell derivatives may be used for lung replacement/regeneration therapeutics and high though-put pharmacological screening strategies for a variety of respiratory injuries and diseases including: cystic fibrosis, chronic obstructive pulmonary disease, respiratory distress syndrome, pulmonary fibrosis and pulmonary edema. This review will explore recent progress in characterizing adult respiratory and bone marrow derived stem cells with respiratory potential as well as the endogenous mechanisms directing the homing of these cells to the diseased and injured lung. In addition, the potential for embryonic stem cell based therapies in this domain as well as the histological, anatomical and molecular aspects of respiratory development will be summarized.
Stem cell therapy: the great promise in lung disease
Ther Adv Respir Dis. 2008 Jun;2(3):173-7.
Source
Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, via S. Maria di Costantinopoli, 16-80138 Napoli, Italy.
dariosin@uab.edu
Abstract
Lung injuries are leading causes of morbidity and mortality worldwide. Pulmonary diseases such as asthma or chronic obstructive pulmonary disease characterized by loss of lung elasticity, small airway tethers, and luminal obstruction with inflammatory mucoid secretions, or idiopathic pulmonary fibrosis characterized by excessive matrix deposition and destruction of the normal lung architecture, have essentially symptomatic treatments and their management is costly to the health care system.Regeneration of tissue by stem cells from endogenous, exogenous, and even genetically modified cells is a promising novel therapy. The use of adult stem cells to help with lung regeneration and repair could be a newer technology in clinical and regenerative medicine. In fact, different studies have shown that bone marrow progenitor cells contribute to repair and remodeling of lung in animal models of progressive pulmonary hypertension.Therefore, lung stem cell biology may provide novel approaches to therapy and could represent a great promise for the future of molecular medicine. In fact, several diseases can be slowed or even blocked by stem cell transplantation.
Mesenchymal stem cells and inflammatory lung diseases
Panminerva Med. 2009 Mar;51(1):5-16.
Source
Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, GA 30322, USA.
Abstract
Mesenchymal stem cells (MSCs) are emerging as a therapeutic modality in various inflammatory disease states. A number of ongoing randomized Phase I/II clinical trials are evaluating the effects of allogeneic MSC infusion in patients with multiple sclerosis, graft-versus-host disease, Crohn's disease, and severe chronic myocardial ischemia. MSCs are also being considered as a potential therapy in patients with inflammatory lung diseases. Several studies, including our own, have demonstrated compelling benefits from the administration of MSCs in animal models of lung injury. These studies are leading to growing interest in the therapeutic use of MSCs in inflammatory lung diseases. In this Review, we describe how the immunoregulatory effects of MSCs can confer substantial protection in the setting of lung diseases such as acute lung injury, chronic obstructive pulmonary disease, asthma, and pulmonary hypertension. We also address potential pitfalls related to the therapeutic use of MSCs in fibrotic lung diseases such as idiopathic pulmonary fibrosis. In addition, we identify emerging areas for MSC- based therapies in modulating oxidative stress and in attenuating inflammation in alcohol-related acute lung injury.
Therapeutic effects of bone marrow-derived mesenchymal stem cells engraftment on bleomycin-induced lung injury in rats
Transplant Proc. 2008 Jun;40(5):1700-5.
Source
Department of Respiratory, Xijing Hospital, Xi'an, China.
Abstract
Previous studies have demonstrated that bone marrow-derived mesenchymal stem cell (MSC) engraftment attenuated lung injury in a model induced by bleomycin in mice. However, the mechanisms are not completely understood. The primary objective of the present study was to determine whether MSC engraftment can also protect lungs against bleomycin-induced injury in rats and to observe any beneficial effects of cytokines. Twelve hours after bleomycin (5 mg/kg) or phosphate-buffered saline was perfused into the trachea, 5x10(6) DAPI-labeled MSCs or DMEM-F12 were injected into the tail vein of rats. Two weeks later, MSCs labeled with DAPI were detected by pan-cytokeratin staining. The level of laminin and hyaluronan in bronchoalveolar lavage fluid was measured by radioimmunoassay. Collagen content in lung tissue was calculated by the hydroxyproline assay. TGF-beta1, PDGF-A, B, and IGF-I were measured by real-time PCR. It was observed that some MSCs positive for pan-cytokeratin staining, an indicator of alveolar epithelial cells, were present in injured lung tissue. Bleomycin injection increased the content of hydroxyproline in lung tissue, as well as laminin and hyaluronan in bronchoalveolar lavage fluid, markers for lung injury and fibrosis. However, these effects were attenuated by MSC treatment. Furthermore, the increased mRNA levels of TGF-beta1, PDGF-A, PDGF-B, and IGF-I following bleomycin injection were also significantly decreased by MSC treatment. These observations provided evidence that MSCs are still present in the lung 2 weeks after the initial MSC treatment in rats, as well as documented the beneficial effects of MSC engraftment against bleomycin-induced lung injury associated with changes in TGF-beta1, PDGF-A, PDGF-B, and IGF-I. These results may provide an experimental base for clinical therapy of pulmonary fibrosis in the future.
Mechanism of Mesenchymal Stem Cells in the Treatment of Asthma
Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2022 Oct;44(5):845-856.
Source
Department of Medicine,Nanchang University,Nanchang 330006,China.
Abstract
Asthma, a chronic inflammatory disease of the respiratory system, is characterized by airway hyperresponsiveness, chronic airway inflammation, mucus secretion, and airway remodelling. Mesenchymal stem cells (MSC) are a kind of multifunctional stem cells, which have the ability of self-renewal and multi-directional differentiation. They are involved in a variety of physiological processes, such as immune response, antigen presentation, inflammatory response, and cell migration. MSCs play a key role in the pathogenesis of bronchial asthma, while the underlying mechanism remains to be studied. MSC are a potential target for the treatment of bronchial asthma. This paper reviews the mechanism of MSC in the treatment of asthma.
Immunomodulatory effects of adipose-derived stem cells in airway allergic diseases
Curr Stem Cell Res Ther. 2010 Jun;5(2):111-5.
Source
Department of ORL-HNS and Medical Research Institute, Pusan National University School of Medicine, Busan, South Korea.
Abstract
Allergic rhinitis and asthma are inflammatory airway allergic diseases caused by Th2-driven immune response. Several studies have shown that multipotent adipose-derived stem cells (ASCs) can exert profound immunosuppressive effects via modulation of both cellular and innate immune pathway, especially immunosuppressive effect on T cell activities. ASCs' ability to be readily isolated from a number of adipose tissues and expanded ex vivo makes them attractive candidate for use in clinical therapy in the context of allogeneic transplantation, in particular to modulate graft-versus-host disease and graft rejection. The authors have investigated whether ASCs can inhibit Th2-dependent airway allergic disease in the mouse model. In this article we review recent experimental data and discuss about the mechanisms by which ASCs inhibit allergic airway inflammation via immunomodulation from a Th2 to a Th1-biased response in the mouse model.
Airway delivery of soluble factors from plastic-adherent bone marrow cells prevents murine asthma
Am J Respir Cell Mol Biol. 2012 Feb;46(2):207-16.
Lavinia I Ionescu, Rajesh S Alphonse, Narcy Arizmendi, Beverly Morgan, Melanie Abel, Farah Eaton, Marek Duszyk, Harissios Vliagoftis, Tamar R Aprahamian, Kenneth Walsh, Bernard Thébaud
Source
University of Alberta, HMRC 407, Edmonton, AB, Canada.
Abstract
Asthma affects an estimated 300 million people worldwide and accounts for 1 of 250 deaths and 15 million disability-adjusted life years lost annually. Plastic-adherent bone marrow-derived cell (BMC) administration holds therapeutic promise in regenerative medicine. However, given the low cell engraftment in target organs, including the lung, cell replacement cannot solely account for the reported therapeutic benefits. This suggests that BMCs may act by secreting soluble factors. BMCs also possess antiinflammatory and immunomodulatory properties and may therefore be beneficial for asthma. Our objective was to investigate the therapeutic potential of BMC-secreted factors in murine asthma. In a model of acute and chronic asthma, intranasal instillation of BMC conditioned medium (CdM) prevented airway hyperresponsiveness (AHR) and inflammation. In the chronic asthma model, CdM prevented airway smooth muscle thickening and peribronchial inflammation while restoring blunted salbutamol-induced bronchodilation. CdM reduced lung levels of the T(H)2 inflammatory cytokines IL-4 and IL-13 and increased levels of IL-10. CdM up-regulated an IL-10-induced and IL-10-secreting subset of T regulatory lymphocytes and promoted IL-10 expression by lung macrophages. Adiponectin (APN), an antiinflammatory adipokine found in CdM, prevented AHR, airway smooth muscle thickening, and peribronchial inflammation, whereas the effect of CdM in which APN was neutralized or from APN knock-out mice was attenuated compared with wild-type CdM. Our study provides evidence that BMC-derived soluble factors prevent murine asthma and suggests APN as one of the protective factors. Further identification of BMC-derived factors may hold promise for novel approaches in the treatment of asthma.
Unraveling the therapeutic effects of mesenchymal stem cells in asthma
Stem Cell Res Ther. 2020 Sep 15;11(1):400.
Source
Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Daneshgah St, Tabriz, 51666-14766, Iran.
Abstract
Asthma is a chronic inflammatory disease associated with airway hyper-responsiveness, chronic inflammatory response, and excessive structural remodeling. The current therapeutic strategies in asthmatic patients are based on controlling the activity of type 2 T helper lymphocytes in the pulmonary tissue. However, most of the available therapies are symptomatic and expensive and with diverse side outcomes in which the interruption of these modalities contributes to the relapse of asthmatic symptoms. Up to date, different reports highlighted the advantages and beneficial outcomes regarding the transplantation of different stem cell sources, and relevant products from for the diseases' alleviation and restoration of injured sites. However, efforts to better understand by which these cells elicit therapeutic effects are already underway. The precise understanding of these mechanisms will help us to translate stem cells into the clinical setting. In this review article, we described current knowledge and future perspectives related to the therapeutic application of stem cell-based therapy in animal models of asthma, with emphasis on the underlying therapeutic mechanisms.
Mesenchymal stem cells exert their anti-asthmatic effects through macrophage modulation in a murine chronic asthma model
Sci Rep. 2022 Jun 13;12(1):9811.
Ruth Lee Kim, Ji-Young Bang, Jeonghyeon Kim, Yosep Mo, Yujin Kim, Chun-Geun Lee, Jack A Elias, Hye Young Kim, Hye-Ryun Kang
Source
Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul National University College of Medicine, Seoul, Korea.
Abstract
Despite numerous previous studies, the full action mechanism of the pathogenesis of asthma remains undiscovered, and the need for further investigation is increasing in order to identify more effective target molecules. Recent attempts to develop more efficacious treatments for asthma have incorporated mesenchymal stem cell (MSC)-based cell therapies. This study aimed to evaluate the anti-asthmatic effects of MSCs primed with Liproxstatin-1, a potent ferroptosis inhibitor. In addition, we sought to examine the changes within macrophage populations and their characteristics in asthmatic conditions. Seven-week-old transgenic mice, constitutively overexpressing lung-specific interleukin (IL)-13, were used to simulate chronic asthma. Human umbilical cord-derived MSCs (hUC-MSCs) primed with Liproxstatin-1 were intratracheally administered four days prior to sampling. IL-13 transgenic mice demonstrated phenotypes of chronic asthma, including severe inflammation, goblet cell hyperplasia, and subepithelial fibrosis. Ly6C+M2 macrophages, found within the pro-inflammatory CD11c+CD11b+ macrophages, were upregulated and showed a strong correlation with lung eosinophil counts. Liproxstatin-1-primed hUC-MSCs showed enhanced ability to downregulate the activation of T helper type 2 cells compared to naïve MSCs in vitro and reduced airway inflammation, particularly Ly6C+M2 macrophages population, and fibrosis in vivo. In conclusion, intratracheal administration is an effective method of MSC delivery, and macrophages hold great potential as an additional therapeutic target for asthma.
Asthma immunotherapy and treatment approaches with mesenchymal stem cells
Immunotherapy. 2020 Jun;12(9):665-674.
Source
Department of Pediatric Allergy & Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey.
Abstract
Asthma is a chronic inflammatory disease of the airways where exaggerated T helper 2 immune responses and inflammatory mediators play a role. Current asthma treatment options can effectively suppress symptoms and control the inflammatory process; however, cannot modulate the dysregulated immune response. Allergen-specific immunotherapy is one of the effective treatments capable of disease modification. Injecting allergens under the skin in allergen-specific immunotherapy can reduce asthma and improve the sensitivity of the lungs, however, has a risk of severe reactions. Mesenchymal stem cells have immunoregulatory activity with their soluble mediators and contact dependent manner. In this review, we focus on the current treatment strategies with mesenchymal stem cells in asthma as a new therapeutic tool and compare those with immunotherapy.
Human mesenchymal stem cells suppress chronic airway inflammation in the murine ovalbumin asthma model
Curr Stem Cell Res Ther. 2010 Jun;5(2):111-5.
Source
Dept. of Pediatrics, Case Western Reserve Univ., Cleveland, OH 44106-4948, USA.
tracey.bonfield@case.edu
Abstract
Allogeneic human mesenchymal stem cells (hMSCs) introduced intravenously can have profound anti-inflammatory activity resulting in suppression of graft vs. host disease as well as regenerative events in the case of stroke, infarct, spinal cord injury, meniscus regeneration, tendinitis, acute renal failure, and heart disease in human and animal models of these diseases. hMSCs produce bioactive factors that provide molecular cuing for: 1) immunosuppression of T cells; 2) antiscarring; 3) angiogenesis; 4) antiapoptosis; and 5) regeneration (i.e., mitotic for host-derived progenitor cells). Studies have shown that hMSCs have profound effects on the immune system and are well-tolerated and therapeutically active in immunocompetent rodent models of multiple sclerosis and stroke. Furthermore, intravenous administration of MSCs results in pulmonary localization. Asthma is a major debilitating pulmonary disease that impacts in excess of 150 million people in the world with uncontrolled asthma potentially leading to death. In addition, the socioeconomic impact of asthma-associated illnesses at the pediatric and adult level are in the millions of dollars in healthcare costs and lost days of work. hMSCs may provide a viable multiaction therapeutic for this inflammatory lung disease by secreting bioactive factors or directing cellular activity. Our studies show the effectiveness and specificity of the hMSCs on decreasing chronic airway inflammation associated with the murine ovalbumin model of asthma. In addition, the results from these studies verify the in vivo immunoeffectiveness of hMSCs in rodents and support the potential therapeutic use of hMSCs for the treatment of airway inflammation associated with chronic asthma.
Mesenchymal stem cells for repair of the airway epithelium in asthma
Expert Rev Respir Med. 2010 Dec;4(6):747-58.
Source
Providence Heart and Lung Institute at St Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada.
darryl.knight@hli.ubc.ca
Abstract
The airway epithelium is constantly faced with inflammatory and potentially injurious stimuli. Following damage, rapid repair mechanisms involving proliferation and differentiation of resident progenitor and stem cell pools are necessary in order to maintain a protective barrier. In asthma, evidence pointing to a compromised ability of the epithelium to properly repair and regenerate is rapidly accumulating. The consequences of this are presently unknown but are likely to have a significant impact on lung function. Mesenchymal stem cells have the potential to serve as a universal source for replacement of specific cells in several diseases and thus offer hope as a potential therapeutic intervention for the treatment of the chronic remodeling changes that occur in the asthmatic epithelium. However, controversy exists regarding whether these cells can actually home to and engraft within the airways and contribute to tissue function or whether this mechanism is necessary, since they can have potent paracrine immunomodulatory effects. This article focuses on the current knowledge about specific stem cell populations that may contribute to airway epithelial regeneration and discusses the use of mesenchymal stem cells as a potential therapeutic intervention.
Induced Pluripotent Stem Cells for Primary Ciliary Dyskinesia Modeling and Personalized Medicine
Am J Respir Cell Mol Biol. 2018 Dec;59(6):672-683.
Joffrey Mianné, Engi Ahmed, Chloé Bourguignon, Mathieu Fieldes, Isabelle Vachier, Arnaud Bourdin, Said Assou, John De Vos
Source
Institute for Regenerative Medicine and Biotherapy, University of Montpellier, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Montpellier, Montpellier, France.
Abstract
Primary ciliary dyskinesia (PCD) is a rare and heterogeneous genetic disorder that affects the structure and function of motile cilia. In the airway epithelium, impaired ciliary motion results in reduced or absent mucociliary clearance that leads to the appearance of chronic airway infection, sinusitis, and bronchiectasis. Currently, there is no effective treatment for PCD, and research is limited by the lack of convenient models to study this disease and investigate innovative therapies. Furthermore, the high heterogeneity of PCD genotypes is likely to hinder the development of a single therapy for all patients. The generation of patient-derived, induced pluripotent stem cells, and their differentiation into airway epithelium, as well as genome editing technologies, could represent major tools for in vitro PCD modeling and for developing personalized therapies. Here, we review PCD pathogenesis and then discuss how human induced pluripotent stem cells could be used to model this disease for the development of innovative, patient-specific biotherapies.