Abstract 3817: Critical Role of Notch1 in Bone Marrow-Derived Stem Cells in Cardiac Regeneration Following Myocardial Infarction
The adult heart has limited regenerative capacity. Bone marrow (BM)-derived stem cells (BMSC) are mobilized to the heart after ischemic injury and contribute to the repair process by reducing cardiomyocyte apoptosis, increasing neovascularization, and partially differentiating into cardiomyocytes. However, the signaling pathway, which mediates this regenerative process, is unknown. Because Notch1 is important for cardiovascular development, we hypothesize that Notch1 in BMSCs may mediate cardiac repair following ischemic injury. To determine the role of Notch1 (N1) in cardiac regeneration, we subjected WT and global heterozygous N1+/− mice to left descending artery (LAD) ligation. Following LAD ligation, mortality was higher for N1+/− mice, and in N1+/− mice that survived, infarct size was larger and heart function was more impaired compared to WT mice. When BM of N1+/− mice was transplanted into WT mice, infarct size was larger, neovascularization was reduced, and heart function was more impaired compared to WT mice transplanted with WT BM. To determine whether N1 in BMSC promotes BMSC mobilization and subsequent differentiation into cardiomyocytes, we crossed transgenic mice expressing GFP with N1+/− mice to generate GFP+/N1+/− mice (GFP-N1+/−). Compared to transplantation with BM from GFP+ mice, WT mice with BM transplanted from GFP-N1+/− mice showed less accumulation of BMSC and decrease presence of GFP-positive cardiomyocytes in the infarct border zone following LAD ligation. Indeed, BMSC derived from N1+/− mice showed strikingly less proliferative capacity, and in a transwell co-culture system with neonatal cardiomyocytes, less migratory ability compared to WT BMSC. When BMSC were directly cultured with neonatal cardiomyocytes, fewer numbers of N1+/− BMSC differentiated into Troponin T-positive cells compared to that of WT BMSC. These findings indicate that Notch1 in BMSC is critically important in the cardiac repair process by facilitating the mobilization, increasing the proliferation, and promoting the differentiation of BMSC. These results suggest that factors or conditions that upregulate Notch1 signaling in BMSC may be therapeutically useful for cardiac regeneration.