Abstract 17765: Embryonic Origin of Adult Resident Cardiac Stem Cells
The recognition that c-kit-positive cardiac stem cells (CSCs) exist in the adult heart raises the important issue of their origin. To answer this question, we have tested the possibility that the pool of CSCs is established during embryonic development and is maintained throughout life. For this purpose, we utilized transgenic mice in which GFP expression is driven by the c-kit promoter. C-kit positive cells were identified at E7.5 in the cardiac crescent and at later stages of embryonic-fetal life. In ex-vivo preparations, time-lapse imaging showed that c-kit positive cardiac cells did not originate by translocation from extracardiac regions. Also, c-kit positive cells were negative for markers of mesenchymal or hematopoietic lineage excluding their origin from primitive sites of hematopoiesis. In vitro, c-kit positive cells obtained from E12-E19 hearts gave rise to multicellular clones composed of cells expressing the stem cell antigen. C-kit positive cells formed myocytes, smooth muscle cells and endothelial cells. The ability to generate myocytes was documented in vivo utilizing a fate mapping approach. C-kit positive cells were obtained from embryos (E18) of mice in which GFP expression was under the control of the α-MHC promoter. Injection of c-kit-positive cells in the infarcted LV of wild-type mice resulted in the formation of GFP-positive myocytes. Collectively, these findings indicate that c-kit-positive cells in the embryonic-fetal heart correspond to bona fide CSCs. Fetal CSCs displayed cytosolic Ca2+ elevations with properties comparable to the oscillatory events observed in adult CSCs. Since Ca2+ cycling regulates the growth of postnatal CSCs, the impact of Ca2+ oscillations on the proliferative capacity of fetal CSCs was established ex vivo. Cultured embryos were exposed to agonist (ATP) or inhibitor (2-APB) of Ca2+ oscillations and BrdU incorporation was evaluated. Induction of Ca2+ oscillations with ATP resulted in a 1.6-fold increase in BrdU incorporation in CSCs. Opposite effects were seen with 2-APB. In conclusion, c-kit-positive CSCs with properties similar to those identified in the adult heart are present in the embryonic heart. Importantly, the proliferative potential of these cells is modulated by Ca2+ oscillations.
- © 2010 by American Heart Association, Inc.