Abstract 14894: Small Molecules Inducing Robust Proliferation of Embryonic Stem Cell or Induced Pluripotent Stem Cell-derived Cardiomyocytes
Backgrounds: Cardiomyocytes derived from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are promising cell sources for cardiac regenerative medicine. However, similar to neonatal or adult cardiomyocytes, ESC/iPSC-derived cardiomyocytes cease proliferation soon after the differentiation to cardiomyocytes. Efficient expansion of ESC/iPSC-derived cardiomyocytes is required and critical for cell-based cardiac regeneration strategies. In this study, to establish a robust cardiomyocyte induction method, we tried to induce cardiomyocyte proliferation using small molecules.
Methods and Results: We screened a synthetic chemical library that contains well-established kinase inhibitors. We treated purified ESC-derived early stage cardiomyocytes with the chemicals and examined the effects on cardiomyocyte proliferation. From this screen, we identified 4 chemicals significantly increasing cardiomyocyte cell number (named Cardiomyocyte Proliferating Chemicals (CPC-1 to 4)). CPC-1 and 4 are a GSK3b inhibitor IX (BIO) and a p38 mitogen activated protein kinase inhibitor (SB203580), respectively. Both of them were reported to increase neonatal and adult cardiomyocytes. Cardiac proliferative effects of CPC-2 and 3 have not been reported. Whereas non-treated cardiomyocytes showed almost no proliferation, each CPC increased cardiomyocyte number by 2–3 folds. An optimal combination of CPCs could enhance the effect up to 7-fold increase in cardiomyocyte number. Cell cycle analysis by the high content imaging demonstrated increases of cardiomyocytes in S-phase and M-phase. CPCs similarly increased proliferation of cardiomyocytes derived from the early mouse embryos or human iPSCs.
Conclusion: We succeeded in identifying synthetic chemicals and their optimized combinations that can efficiently induce cardiomyocyte proliferation. These findings would largely contribute to future cardiac regenerative medicine.
- © 2010 by American Heart Association, Inc.