Stem Cell Factor Gene Transfer Promotes Cardiac Repair After Myocardial Infarction via In Situ Recruitment and Expansion of c-kit+ Cells

• Published in: Circulation research Vol. 111; no. 11; pp. 1434 - 1445
• Main Authors: Yaniz-Galende, Elisa, Chen, Jiqiu, Chemaly, Elie, Liang, Lifan, Hulot, Jean-Sebastien, McCollum, LaTronya, Arias, Teresa, Fuster, Valentin, Zsebo, Krisztina M, Hajjar, Roger J
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 09.11.2012; Lippincott Williams & Wilkins
• Subjects: Adenoviridae - genetics; Animals; beta Catenin - genetics; beta Catenin - metabolism; Biological and medical sciences; Blotting, Western; Cardiology. Vascular system; Cell Count; Cell Proliferation; Coronary heart disease; Fundamental and applied biological sciences. Psychology; Gene Expression; Genetic Therapy - methods; Heart; Humans; Kaplan-Meier Estimate; Male; Medical sciences; Microscopy, Confocal; Myocardial Infarction - genetics; Myocardial Infarction - physiopathology; Myocardial Infarction - therapy; Myocarditis. Cardiomyopathies; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - metabolism; Proto-Oncogene Proteins c-kit - metabolism; Rats; Rats, Sprague-Dawley; Regeneration; Reverse Transcriptase Polymerase Chain Reaction; Stem Cell Factor - genetics; Stem Cell Factor - metabolism; Stem Cells - metabolism; Vertebrates: cardiovascular system; Wnt Signaling Pathway - genetics; Myocardial infarction; cardiac myocyte regeneration; stem cell factor; gene transfer; In situ; Cardiovascular disease; Coronary heart disease; Myocardial disease; Myocyte; Recruitment; Genetic transfer; Regeneration; Vertebrata; Mammalia; Circulatory system; Mast cell growth factor; Repair
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.111.263830

RATIONALE:There is growing evidence that the myocardium responds to injury by recruiting c-kit cardiac progenitor cells to the damage tissue. Even though the ability of exogenously introducing c-kit cells to injured myocardium has been established, the capability of recruiting these cells through modulation of local signaling pathways by gene transfer has not been tested. OBJECTIVE:To determine whether stem cell factor gene transfer mediates cardiac regeneration in a rat myocardial infarction model, through survival and recruitment of c-kit progenitors and cell-cycle activation in cardiomyocytes, and explore the mechanisms involved. METHODS AND RESULTS:Infarct size, cardiac function, cardiac progenitor cells recruitment, fibrosis, and cardiomyocyte cell-cycle activation were measured at different time points in controls (n=10) and upon stem cell factor gene transfer (n=13) after myocardial infarction. We found a regenerative response because of stem cell factor overexpression characterized by an enhancement in cardiac hemodynamic functionan improvement in survival; a reduction in fibrosis, infarct size and apoptosis; an increase in cardiac c-kit progenitor cells recruitment to the injured area; an increase in cardiomyocyte cell-cycle activation; and Wnt/β-catenin pathway induction. CONCLUSIONS:Stem cell factor gene transfer induces c-kit stem/progenitor cell expansion in situ and cardiomyocyte proliferation, which may represent a new therapeutic strategy to reverse adverse remodeling after myocardial infarction.