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(Circulation. 2007;116:I-77 – I-82.)
© 2007 American Heart Association, Inc.

Cell Transplantation and Tissue Regeneration

c-Kit Dysfunction Impairs Myocardial Healing After Infarction

Massimo Cimini, PhD; Shafie Fazel, MD, PhD; Sun Zhuo, MD; Munira Xaymardan, MD, PhD; Hiroko Fujii, MD, PhD; Richard D. Weisel, MD; Ren-Ke Li, MD, PhD

From the Division of Cardiovascular Surgery, Toronto General Hospital, University Health Network, University of Toronto, Ontario, Canada.

Correspondence to Ren-Ke Li, MaRS Centre, Toronto Medical Discovery Tower, Room #3-702, 101 College St, Toronto, ON, Canada, M5G 1L7. E-mail renkeli{at}uhnres.utoronto.ca

Background— We hypothesized that c-kit receptor function in the bone marrow is important for facilitating healing, leading to efficient cardiac repair after myocardial infarction (MI).

Methods and Results— We used Kit^W/Kit^W-v c-kit mutant mice and their wild-type littermates to assess the importance of c-kit function in cardiac remodeling after coronary ligation. We found that mutant mice developed 1.6-fold greater ventricular dilation (P=0.008) attributable to a 1.3-fold greater infarct expansion by day 14 after MI (P=0.01). The number of proliferating smooth muscle -actin expressing cells was 1.8-fold lower in mutant mice at day 3 (P<0.01), resulting in a 1.6 to 1.8-fold reduction in total regional nonvascular smooth muscle -actin expressing cells by both microscopy and flow cytometry (P<0.001 for both). This decrease was accompanied by a 1.4-fold reduction in the number of CD31 expressing blood vessels (P<0.05). Prior transplantation of wild-type bone marrow cells into mutant mice rescued the efficient establishment of vessel-rich repair tissue by inducing a 1.5-fold increase in nonvascular smooth muscle -actin expressing cells and CD31 expressing blood vessels (P<0.05 for both). The increased recruitment of cells into the infarct region in the chimeric mice was associated with reduced infarct expansion (P<0.03) compared to wild-type levels.

Conclusions— Bone marrow c-kit function critically impacts the myofibroblast repair response in infarcted hearts. Interventions that increase the infiltration of c-kit⁺ cells to the infarcted heart may potentiate this endogenous repair response, prevent infarct expansion, and improve the recovery of cardiac function after MI.

Key Words: c-kit • myofibroblast • myocardial infarction • cardiac remodeling