Duchenne Muscular Dystrophy (DMD) is a lethal muscle wasting disease caused by the lack of dystrophin, which eventually leads to apoptosis of muscle cells and impaired muscle contractility. Induced pluripotent stem cells (iPSC) offer the potential to correct the DMD gene defect and create healthy cells for transplantation without causing immune activation. However, this requires engineering iPSCs to facilitate homing and engraftment into diseased muscle tissue without promoting tumorigenesis. Our long-term goal is to optimize the differentiation of iPSC into myogenic progenitor cells (MPC) that are directed to home into muscle tissue and engraft without undergoing unrestrained growth. Our central hypothesis is that precise MPC genetic engineering, coupled with targeted modification of the host muscle niche by preconditioning or exosome delivery, will boost homing and engraftment of donor iPSC-derived MPC via the SDF-CXCR4 axis to safely and effectively treat DMD. The rationale is to develop methodology to produce large quantities of functional MPC from patients with DMD that are tumor free and can effectively home to sites of muscle injury and facilitate repair. We plan to test our central hypothesis and accomplish the objectives of this application by pursuing the following three specific aims.
In Aim 1, we will test the hypothesis that iPSC-derived progenitor cells are effective and safe for regeneration of dystrophic muscle.
In Aim 2, we will test the hypothesis that activation of CXCR4 in iPSC-derived myogenic precursors from DMD mice using a CRISPR-on based genomic platform improves engraftment of donor cells in DMD mice.
In Aim 3, we will test the hypothesis that optimizing the regenerative microenvironment in muscle by ischemic preconditioning or iPSC-exosome-mediated delivery of SDF-1? protein enhances the homing and/or survival of donor MPC to augment muscle repair. These experiments have the potential to demonstrate that transplantation of iPSC-derived progenitors, coupled with methods to optimize the host muscle microenvironment, will more effectively ameliorate dystrophic pathology and improve the quality of life for patients with DMD.

Public Health Relevance

Duchenne Muscular Dystrophy is a genetic disease that causes progressive muscle weakness and death in young men. This proposal will establish novel methods for producing myogenic progenitors derived from integration-free induced pluripotent stem cells (iPSC), their mobilization, and engraftment into the dystrophic muscle for restoring normal muscle population.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Cheever, Thomas
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Augusta University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Ruan, Xiao-Fen; Li, Yong-Jun; Ju, Cheng-Wei et al. (2018) Exosomes from Suxiao Jiuxin pill-treated cardiac mesenchymal stem cells decrease H3K27 demethylase UTX expression in mouse cardiomyocytes in vitro. Acta Pharmacol Sin 39:579-586
Benson, Tyler W; Weintraub, Daniel S; Crowe, Matthew et al. (2018) Deletion of the Duffy antigen receptor for chemokines (DARC) promotes insulin resistance and adipose tissue inflammation during high fat feeding. Mol Cell Endocrinol 473:79-88
Xuan, Wanling; Wang, Yan; Tang, Yaoliang et al. (2018) Cardiac Progenitors Induced from Human Induced Pluripotent Stem Cells with Cardiogenic Small Molecule Effectively Regenerate Infarcted Hearts and Attenuate Fibrosis. Shock 50:627-639
Bayoumi, Ahmed S; Aonuma, Tatsuya; Teoh, Jian-Peng et al. (2018) Circular noncoding RNAs as potential therapies and circulating biomarkers for cardiovascular diseases. Acta Pharmacol Sin 39:1100-1109
Ju, Chengwei; Shen, Yan; Ma, Gengshan et al. (2018) Transplantation of Cardiac Mesenchymal Stem Cell-Derived Exosomes Promotes Repair in Ischemic Myocardium. J Cardiovasc Transl Res 11:420-428
Wang, Zi; Su, Xuan; Ashraf, Muhammad et al. (2018) Regenerative Therapy for Cardiomyopathies. J Cardiovasc Transl Res :
Ruan, Xiao-Fen; Ju, Cheng-Wei; Shen, Yan et al. (2018) Suxiao Jiuxin pill promotes exosome secretion from mouse cardiac mesenchymal stem cells in vitro. Acta Pharmacol Sin 39:569-578
Lino Cardenas, Christian L; Kessinger, Chase W; Cheng, Yisha et al. (2018) An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm. Nat Commun 9:1009
Murphy, Cameron; Withrow, Joseph; Hunter, Monte et al. (2018) Emerging role of extracellular vesicles in musculoskeletal diseases. Mol Aspects Med 60:123-128
Tang, Yaoliang; Lei, Wei; Chen, Yanfang et al. (2018) Noncoding RNAs and Stem Cell Function and Therapy. Stem Cells Int 2018:7306034

Showing the most recent 10 out of 26 publications