Stem cell factor receptor induces progenitor and natural killer cell-mediated cardiac survival and repair after myocardial infarction.
Inappropriate cardiac remodeling and repair after myocardial infarction (MI) predisposes to heart failure. Studies have reported on the potential for lineage negative, steel factor positive (c-kit+) bone marrow-derived hematopoetic stem/progenitor cells (HSPCs) to repair damaged myocardium through neovascularization and myogenesis. However, the precise contribution of the c-kit signaling pathway to the cardiac repair process has yet to be determined. In this study, we sought to directly elucidate the mechanistic contributions of c-kit+ bone marrow-derived hematopoetic stem/progenitor cells in the maintenance and repair of damaged myocardium after MI. Using c-kit-deficient mice, we demonstrate the importance of c-kit signaling in preventing ventricular dilation and hypertrophy, and the maintenance of cardiac function after MI in c-kit-deficient mice. Furthermore, we show phenotypic rescue of cardiac repair after MI of c-kit-deficient mice by bone marrow transplantation of wild-type HSPCs. The transplanted group also had reduced apoptosis and collagen deposition, along with an increase in neovascularization. To better understand the mechanisms underlying this phenotypic rescue, we investigated the gene expression pattern within the infarcted region by using microarray analysis. This analysis suggested activation of inflammatory pathways, specifically natural killer (NK) cell-mediated mobilization after MI in rescued hearts. This finding was confirmed by immunohistology and by using an NK blocker. Thus, our investigation revealed a previously uncharacterized role for c-kit signaling after infarction by mediating bone marrow-derived NK and angiogenic cell mobilization, which contributes to improved remodeling and cardiac function after MI.
Ayach
Bilal B
BB
Toronto General Hospital Research Institute and Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C4.
Yoshimitsu
Makoto
M
Dawood
Fayez
F
Sun
Mei
M
Arab
Sara
S
Chen
Manyin
M
Higuchi
Koji
K
Siatskas
Christopher
C
Lee
Paul
P
Lim
Hilda
H
Zhang
Jane
J
Cukerman
Eva
E
Stanford
William L
WL
Medin
Jeffrey A
JA
Liu
Peter P
PP
D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D016026:Bone Marrow Transplantation; D005260:Female; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D007694:Killer Cells, Natural / Q000502:physiology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009203:Myocardial Infarction / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000235:genetics*
D019009:Proto-Oncogene Proteins c-kit