| Title | Timely Inhibition of Notch Signaling by DAPT Promotes Cardiac Differentiation of Murine Pluripotent Stem Cells |
| Authors | Liu, Yinan Li, Peng Liu, Kaiyu He, Qihua Han, Shuo Sun, Xiaofeng Li, Tao Shen, Li |
| Affiliation | Peking Univ, Sch Basic Med Sci, Dept Cell Biol, Stem Cell Res Ctr, Beijing 100871, Peoples R China. Peking Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Beijing 100871, Peoples R China. Peking Univ, Sch Basic Med Sci, Ctr Med & Hlth Anal, Beijing 100871, Peoples R China. Hunan Univ Chinese Med, Inst Chinese Med, Dept Histol & Embryol, Changsha, Hunan, Peoples R China. Zhejiang Normal Univ, Coll Chem & Life Sci, Dept Biol, Jinhua, Zhejiang, Peoples R China. |
| Keywords | HUMAN SOMATIC-CELLS PROGENITOR CELLS NEURONAL DIFFERENTIATION WNT/BETA-CATENIN CARDIOMYOGENESIS CARDIOMYOCYTES PROTEIN MOUSE HEART STAGE |
| Issue Date | 2014 |
| Publisher | plos one |
| Citation | PLOS ONE.2014,9,(10). |
| Abstract | The Notch signaling pathway plays versatile roles during heart development. However, there is contradictory evidence that Notch pathway either facilitates or impairs cardiomyogenesis in vitro. In this study, we developed iPSCs by reprogramming of murine fibroblasts with GFP expression governed by Oct4 promoter, and identified an effective strategy to enhance cardiac differentiation through timely modulation of Notch signaling. The Notch inhibitor DAPT (N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester) alone drove the iPSCs to a neuronal fate. After mesoderm induction of embryoid bodies initiated by ascorbic acid (AA), the subsequent treatment of DAPT accelerated the generation of spontaneously beating cardiomyocytes. The timed synergy of AA and DAPT yielded an optimal efficiency of cardiac differentiation. Mechanistic studies showed that Notch pathway plays a biphasic role in cardiomyogenesis. It favors the early-stage cardiac differentiation, but exerts negative effects on the late-stage differentiation. Therefore, DAPT administration at the late stage enforced the inhibition of endogenous Notch activity, thereby enhancing cardiomyogenesis. In parallel, DAPT dramatically augmented the expression of Wnt3a, Wnt11, BMP2, and BMP4. In conclusion, our results highlight a practicable approach to generate cardiomyocytes from iPSCs based on the stage-specific biphasic roles of Notch signaling in cardiomyogenesis. |
| URI | http://hdl.handle.net/20.500.11897/188910 |
| ISSN | 1932-6203 |
| DOI | 10.1371/journal.pone.0109588 |
| Indexed | SCI(E) PubMed |
| Appears in Collections: | 基础医学院 |
