Induced Pluripotent Stem Cells derived Muscle Progenitors Effectively Mitigate Muscular Dystrophy through Restoring the Dystrophin Distribution

Background Duchenne Muscular Dystrophy (DMD) is a recessive form of muscular disorder, resulting from the dystrophin gene mutations in X-chromosome. Application of embryonic stem cells or adult stem cells has demonstrated the therapeutic effects on DMD through both cell-based and non-cell based mechanisms. In this study, we proposed that Myogenic Progenitor Cells from Induced Pluripotent Stem Cells (iPSC-MPCs) would be more effective in repairing muscle damage caused by muscular dystrophy. Methods and results Mouse iPSCs were cultured in myogenic differentiation culture medium and the MPCs were characterized using Reverse Transcription Polymerase Chain Reaction (RT-PCR) and flow cytometry. iPSCs were successfully converted into MPCs, as evidenced by the distinct expression of myogenic genes and cell surface markers. The muscle injury was induced in tibialis muscle of mdx mouse by cardiotoxin injection, and the iPSC-MPCs were then engrafted into the damage site. Firefly luciferase expression vector was transduced into iPSC-MPCs and the in vivo bioluminescence imaging analysis revealed that these progenitor cells survived even at 30-days post transplantation. Importantly, histological analysis revealed that the central nuclei percentage, as well as fibrosis, was significantly reduced in the iPSC-MPCs treated muscle. In addition,the transplantation of progenitor cells restored the distributions of dystrophin and nicotinic acetylcholine receptors together with up-regulation of pair box protein 7(Pax7), a myogenic transcription factor. Conclusion iPSCs-derived MPCs exert strong therapeutic effects on muscular dystrophy by restoring dystrophin expression and acetylcholine receptor distribution.

[1]  A. Bigot,et al.  Invited review: Stem cells and muscle diseases: advances in cell therapy strategies , 2015, Neuropathology and applied neurobiology.

[2]  N. Hanley,et al.  Generation of Distal Airway Epithelium from Multipotent Human Foregut Stem Cells , 2015, Stem cells and development.

[3]  N. Desai,et al.  Human embryonic stem cell cultivation: historical perspective and evolution of xeno-free culture systems , 2015, Reproductive Biology and Endocrinology.

[4]  W. Stanford,et al.  Derivation and Expansion of PAX7-Positive Muscle Progenitors from Human and Mouse Embryonic Stem Cells , 2014, Stem Cell Reports.

[5]  W. Stanford,et al.  Derivation and Expansion of PAX7-Positive Muscle Progenitors from Human and Mouse Embryonic Stem Cells , 2014, Stem cell reports.

[6]  M. Bouché,et al.  From Innate to Adaptive Immune Response in Muscular Dystrophies and Skeletal Muscle Regeneration: The Role of Lymphocytes , 2014, BioMed research international.

[7]  J. Chamberlain,et al.  Gene and cell‐mediated therapies for muscular dystrophy , 2013, Muscle & nerve.

[8]  Chun Zhang,et al.  Gold clusters on Nb-doped SrTiO3: effects of metal-insulator transition on heterogeneous Au nanocatalysis. , 2012, Physical chemistry chemical physics : PCCP.

[9]  Tracy J. Pritchard,et al.  Ablation of junctin or triadin is associated with increased cardiac injury following ischaemia/reperfusion. , 2012, Cardiovascular research.

[10]  M. Ashraf,et al.  Reduced collagen deposition in infarcted myocardium facilitates induced pluripotent stem cell engraftment and angiomyogenesis for improvement of left ventricular function. , 2011, Journal of the American College of Cardiology.

[11]  T. Wynn,et al.  Fibrosis is regulated by Th2 and Th17 responses and by dynamic interactions between fibroblasts and macrophages. , 2011, American journal of physiology. Gastrointestinal and liver physiology.

[12]  R. Hajjar,et al.  Mitigation of muscular dystrophy in mice by SERCA overexpression in skeletal muscle. , 2011, The Journal of clinical investigation.

[13]  Hannele Ruohola-Baker,et al.  Chronic Hypoxia Impairs Muscle Function in the Drosophila Model of Duchenne's Muscular Dystrophy (DMD) , 2010, PloS one.

[14]  J. Bassaganya-Riera,et al.  Immune‐Mediated Mechanisms Potentially Regulate the Disease Time‐Course of Duchenne Muscular Dystrophy and Provide Targets for Therapeutic Intervention , 2009, PM & R : the journal of injury, function, and rehabilitation.

[15]  J. Chamberlain,et al.  Emerging strategies for cell and gene therapy of the muscular dystrophies , 2009, Expert Reviews in Molecular Medicine.

[16]  Angela K. Peter,et al.  Disrupted mechanical stability of the dystrophin-glycoprotein complex causes severe muscular dystrophy in sarcospan transgenic mice , 2007, Journal of Cell Science.

[17]  Daniel J Garry,et al.  Muscle stem cells in development, regeneration, and disease. , 2006, Genes & development.

[18]  I. Weissman,et al.  Isolation of Adult Mouse Myogenic Progenitors Functional Heterogeneity of Cells within and Engrafting Skeletal Muscle , 2004, Cell.

[19]  N. Bresolin,et al.  Identification of a putative pathway for the muscle homing of stem cells in a muscular dystrophy model , 2003, The Journal of cell biology.

[20]  D. Price,et al.  Membrane myopathy: Morphological similarities to duchenne muscular dystrophy , 1982, Muscle & nerve.

[21]  M. Rudnicki,et al.  Pax7 activates myogenic genes by recruitment of a histone methyltransferase complex , 2008, Nature Cell Biology.

[22]  M. Rudnicki,et al.  The molecular regulation of muscle stem cell function. , 2008, Cold Spring Harbor symposia on quantitative biology.