Activation of c-kit is necessary for mobilization of reparative bone marrow progenitor cells in response to cardiac injury.
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
Shafie S
SS
Division of Cardiac Surgery, Department of Surgery, Toronto General Hospital Research Institute, Toronto, ON, Canada, M5G 1L7.
Chen
Liwen
L
Angoulvant
Denis
D
Li
Shu-Hong
SH
Weisel
Richard D
RD
Keating
Armand
A
Li
Ren-Ke
RK
D000818:Animals; D001853:Bone Marrow / Q000201:enzymology*; D002465:Cell Movement; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000097:blood / Q000201:enzymology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D019089:Stem Cell Factor / Q000097:blood / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D015854:Up-Regulation
D012333:RNA, Messenger; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit; D020780:Matrix Metalloproteinase 9