Abstract 5632: Cardiac Repair Following Myocardial Injury is Mediated by Notch1 Signaling in Mesenchymal Stem Cells

Abstract

Background: Notch receptors regulate binary cell fate determination and are critical for embryonic development. In particular, Notch1 regulates the fate of cardiac progenitor cells and is an important mediator of vasculogenesis. However, it is little known whether Notch1 could contribute to the cardiac repair process following myocardial injury. Methods and Results: We generated mutant mice with cardiac-specific deletion of Notch1 ( α MHC-Cre/Notch1 flox/flox mice, C-N1−/−). After left descending artery (LAD) ligation, infarct size, cardiac dimension, and heart function were similar between C-N1−/− mice and control mice. However, global heterozygous Notch1 (N1+/−) mice exhibited larger infarct size, greater LV dimension, and worsening LV function compared to that of WT mice. These findings suggest that non-cardiac Notch1 contributes to cardiac repair. When the bone marrow (BM) of N1+/− mice was transplanted into WT mice, infarct size, and impaired heart function were greater, vascularity in the infarct border area was reduced, compared to WT mice transplanted with WT BM. Alternatively, WT BM transplantation (BMT) could rescue the increased myocardial injury observed in N1+/− mice. Using GFP labeled BM cell, we found more mesenchymal stem cells (MSCs) from WT BM could be recruited to the heart compared to that of N1+/− BM. Notch1 deficient also prevent the differentiation of BM-derived cells into vascular cells. In vitro, compared to WT MSCs, N1+/− MSCs showed less migration and proliferative capacity. When N1+/− MSCs were intramyocardially injected into the infarct heart of WT mice, infarct size was greater and blood vessel density was reduced compared that of WT MSCs. Indeed, N1+/− MSCs showed decreased survival after injection compared to WT MSCs. Furthermore, the expression of Notch1 target genes, Hey1 and HeyL, and cytokine receptors CSF3R and CXCR4 were reduced in N1+/− MSCs. This decrease was reversed by overexpression of Notch1 intracellular domain. Conclusions: These findings indicate that Notch signaling in MSC is critical for cardiac repair after myocardial infarction, and suggest that therapeutic strategies that increase Notch1 signaling in MSC could have clinical benefits in patients with ischemic heart disease.