Cardiac Protection after Systemic Transplant of Dystrophin Expressing Chimeric (DEC) Cells to the mdx Mouse Model of Duchenne Muscular Dystrophy

Abstract

Duchenne Muscular Dystrophy (DMD) is a progressive lethal disease caused by X-linked mutations of the dystrophin gene. Dystrophin deficiency clinically manifests as skeletal and cardiac muscle weakness, leading to muscle wasting and premature death due to cardiac and respiratory failure. Currently, no cure exists. Since heart disease is becoming a leading cause of death in DMD patients, there is an urgent need to develop new more effective therapeutic strategies for protection and improvement of cardiac function. We previously reported functional improvements correlating with dystrophin restoration following transplantation of Dystrophin Expressing Chimeric Cells (DEC) of myoblast origin in the mdx and mdx/scid mouse models. Here, we confirm positive effect of DEC of myoblast (MB wt /MB mdx ) and mesenchymal stem cells (MB wt /MSC mdx ) origin on protection of cardiac function after systemic DEC transplant. Therapeutic effect of DEC transplant (0.5 × 10 6 ) was assessed by echocardiography at 30 and 90 days after systemic-intraosseous injection to the mdx mice. At 90 days post-transplant, dystrophin expression in cardiac muscles of DEC injected mice significantly increased (15.73% ± 5.70 -MB wt /MB mdx and 5.22% ± 1.10 -MB wt /MSC mdx DEC) when compared to vehicle injected controls (2.01% ± 1.36) and, correlated with improved ejection fraction and fractional shortening on echocardiography. DEC lines of MB and MSC origin introduce a new promising approach based on the combined effects of normal myoblasts with dystrophin delivery capacities and MSC with immunomodulatory properties. Our study confirms feasibility and efficacy of DEC therapy on cardiac function and represents a novel therapeutic strategy for cardiac protection and muscle regeneration in DMD.

Human Dystrophin Expressing Chimeric (DEC) Cell Therapy Ameliorates Cardiac, Respiratory, and Skeletal Muscle's Function in Duchenne Muscular Dystrophy

“…These DEC lines were successfully tested in the preclinical models of mdx and mdx/scid mice. [41][42][43] We confirmed increase in dystrophin expression which correlated with significant improvement of muscle strength and function at 90 days after DEC transplant. 42 In a search of the "perfect" donor cell for skeletal muscle regeneration, researchers agreed that the cell candidate should be easily accessible, able to expand, engraft, preserve myogenic phenotype, and display a high survival rate.…”

“…Our DEC cells fulfill the prerequisites of the preferred MB therapy candidates, since DEC are of MB origin, are easily accessible and expandable, preserve myogenic phenotype in culture, and are characterized by long-term engraftment without the need of supportive immunosuppression. [41][42][43] However, in order to elicit therapeutic effect, the most important factors responsible for efficacy of MB-based therapy include long-term MB engraftment and the route of MB administration. Most of the experimental and clinical studies testing MB therapeutic effect in DMD were based on local intramuscular MBs delivery.…”

“…41,42 Moreover, systemic intraosseous DEC transplantation confirmed protective effect on cardiac function by the rebound effect on the ejection fraction (EF) and fractional shortening (FS). 43 In the current study, we aimed to demonstrate that systemicintraosseous transplantation of human DEC cells will elicit target organoriented systemic effect and will protect the DMD-affected cardiac, respiratory, and skeletal muscles from progressive functional decline.…”

Development of Donor Recipient Chimeric Cells of bone marrow origin as a novel approach for tolerance induction in transplantation

“…Multiple studies described involvement of cell fusion in tissue regeneration (6,12,24,25,32,33) encouraging development of fusion-based cell lines and therapies for research and clinical applications (2,(34)(35)(36)(37)(38)(39)(40). The presence of donor/ recipient cells observed in the clinical BMT studies (41)(42)(43) was explained by spontaneous fusion of donor HSC with cells of BMT recipient or by trogocytosis, a process of intercellular transfer of membrane patches or proteins (44)(45)(46)(47).…”

Dystrophin Deficiency Causes Progressive Depletion of Cardiovascular Progenitor Cells in the Heart

“…The reason of such difference between mouse and human CVPCs is unknown and would require further experiments. Based on several previous studies, including ours, mdx mice developed cardiac dysfunction by 20 wo, with myocardial fibrosis, increased collagen expression, ventricular hypertrophy, and arrhythmias as well as left ventricular dysfunction [ 13 , 64 , 65 , 66 , 67 , 68 ]. These studies clearly support the age-dependent cardiac dysfunction in the mdx mice.…”