Abstract 913: Contribution of Bone Marrow-Derived Cells on Pressure Overload-Induced Cardiac Hypertrophy and Perivascular Fibrosis in Mice
Pathological cardiac hypertrophy is accompanied with cardiomyocyte loss and reactive perivascular fibrosis. Previously, we reported that bone marrow (BM) derived cells regenerate cardiomyocytes prominently through cell fusion when mice were subjected to pulmonary hypertension induced by prolonged hypoxia. However, it remains elusive whether pressure-overload itself suffices to regenerate cardiomyocytes from BM-cells. Here, we designed to investigate whether BM-derived cells contribute to the regeneration of cardiomyocytes and reactive perivascular fibrosis in response to pressure-overload induced by transverse aortic constriction (TAC). [Methods and Results] Lethally irradiated wild-type mice had their BM cells reconstituted with unfractionated BM cells from green fluorescent protein (GFP) transgenic mice. Eight weeks after transplantation, BM transplanted mice with high chimerism were subjected to TAC. The chimera mice were analyzed 2 and 4 weeks after TAC. GFP+/α-actinin+ BM-derived cardiomyocytes were observed only when the mice were subjected to TAC. BM-derived cardiomyocytes were existed almost exclusively in either LV free wall or septum, and none of them were detectable in right ventricular free wall. BM-derived cardiomyocytes were detectable from 2 weeks after TAC, and the number of BM-derived cardiomyocytes was increased with time after TAC. Perivascular fibrosis became evident 4 weeks after TAC. GFP+/CD11b+/CD14+ BM-derived monocytes were accumulated around the vasculature. Both GFP− and GFP+ fibroblast-like cells were existed in the perivascular region. These cells expressed both vimentin and α-smooth muscle actin, indicating myofibroblasts. Only GFP+ myofibloblasts coexpressed CD11b+ and/or CD14+. [Conclusion] Pressure-overload triggers the homing and differentiation of BM derived cells into cardiomyocytes. BM-derived monocytes infiltrate in the perivascular region and differentiate into myofibroblasts. These findings indicate that not only cells residing myocardium, but also BM-derived cells contributed to the pathogenesis of cardiac hypertrophy in response to pressure-overload through both regeneration of cardiomyocytes and formation of perivascular fibrosis.