Faculty Collaboration Database

Stem cell factor receptor induces progenitor and natural killer cell-mediated cardiac survival and repair after myocardial infarction. Proc Natl Acad Sci U S A 2006 Feb 14;103(7):2304-9

Date

02/10/2006

Pubmed ID

16467148

Pubmed Central ID

PMC1413746

DOI

10.1073/pnas.0510997103

Scopus ID

2-s2.0-33144455158 (requires institutional sign-in at Scopus site)   105 Citations

Abstract

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.

Author List

Ayach BB, Yoshimitsu M, Dawood F, Sun M, Arab S, Chen M, Higuchi K, Siatskas C, Lee P, Lim H, Zhang J, Cukerman E, Stanford WL, Medin JA, Liu PP

Author

Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Bone Marrow Cells
Bone Marrow Transplantation
Female
Gene Expression Profiling
Hematopoietic Stem Cells
Killer Cells, Natural
Male
Mice
Mice, Mutant Strains
Mutation
Myocardial Infarction
Neovascularization, Physiologic
Proto-Oncogene Proteins c-kit
Ventricular Remodeling