Stem cell factor receptor induces progenitor and natural killer cell-mediated cardiac survival and repair after myocardial infarction

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 stem͞progenitor 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 stem͞ 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.hematopoetic stem progenitor cells ͉ steel factor receptor ͉ angiogenesis

Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium

“…The current study demonstrated that CXCR4 overexpressing MSCs increase the expression of ckit. This is of potential importance because c-kit positive cells play a significant contributing role in cardiac repair and restoration of heart function after myocardial infarction [24]. The significance of the increased number of c-kit positive cells further underscores the factor that c-kit deficient cardiac progenitor cells in W/W v mice prevent cell differentiation during aging or after injury [24] and that c-kit positive cells are also associated with enhanced angiogenesis [25].…”

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

“…Concerns about inhibiting KIT were raised recently by studies of the Kit W/W-v mouse, a compound heterozygote in which one allele is deleted and the other has reduced kinase activity. This mouse, when subjected to myocardial infarction, had markedly impaired postmyocardial infarction repair and survival, which was attributed to failure to recruit bone-marrow-derived stem/progenitor cells that are pro-angiogenic to the infarct zone 89,90 . This raises concerns that inhibition of KIT might aggravate pathological remodelling of the heart postmyocardial infarction and prevent repair.…”

Induction of Cardiac Angiogenesis Requires Killer Cell Lectin-Like Receptor 1 and α4β7 Integrin Expression by NK Cells

“…Our data demonstrate that the absence of cardiac-infiltrating lymphoid cells is associated with a poorer outcome. Previous publications underlined the importance of NK cell dependence in heart recovery following MI (17). In their study, Ayach and coworkers (17) showed that specific NK cell depletion in immune-competent mice reduced their survival by 30% as a result of heart failure.…”

“…It is an inhibitor of IL-1, IL-6, IL-8, and TNF-a production and has been reported to modulate the function and phenotype of monocytes/macrophages (15,16). In a recent study, it was shown that c-kit-mediated mobilization of bone marrow NK cells rescues hearts post-myocardial infarction (MI), contributing to improved remodeling and cardiac function (17). The literature is, however, missing the precise mechanism of NK cellmediated cardiac repair following infarction.…”