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Activation of c-kit is necessary for mobilization of reparative bone marrow progenitor cells in response to cardiac injury

Shafie S. Fazel^*, Liwen Chen^*, Denis Angoulvant^*, Shu-Hong Li^*, Richard D. Weisel^*, Armand Keating and Ren-Ke Li^*,1

^* Division of Cardiac Surgery, Department of Surgery, Toronto General Hospital Research Institute, and

Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada

¹Correspondence: Toronto General Hospital, MaRS Centre, Toronto Medical Discovery Tower, Rm. 3–702, 101 College St., Toronto, ON, Canada, M5G 1L7, E-mail: renkeli{at}uhnres.utoronto.ca

Cardiovascular disease is the number-one cause of mortality in the developed world. The aim of this study is to define the mechanisms by which bone marrow progenitor cells are mobilized in response to cardiac ischemic injury. We used a closed-chest model of murine cardiac infarction/reperfusion, which segregated the surgical thoracotomy from the induction of cardiac infarction, so that we could study isolated fluctuations in cytokines without the confounding impact of surgery. We show here that bone marrow activation of the c-kit tyrosine kinase receptor in response to released soluble KitL is necessary for bone marrow progenitor cell mobilization after ischemic cardiac injury. We also show that release of KitL and c-kit activation require the activity of matrix metalloproteinase-9 within the bone marrow compartment. Finally, we demonstrate that mice with c-kit dysfunction develop cardiac failure after myocardial infarction and that bone marrow transplantation rescues the failing cardiac phenotype. In light of the ongoing trials of progenitor cell therapy for heart disease, our study outlines the endogenous repair mechanisms that are invoked after cardiac injury. Amplification of this pathway may aid in restoration of cardiac function after myocardial infarction.—Fazel, S. S., Chen, L., Angoulvant, D., Li, S. H., Weisel, R. D., Keating, A., Li, R. K. Activation of c-kit is necessary for mobilization of reparative bone marrow progenitor cells in response to cardiac injury.

Key Words: myocardial infarction • heart failure • stem cells • cell signaling