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学科主题: 基础医学
题名:
Timely Inhibition of Notch Signaling by DAPT Promotes Cardiac Differentiation of Murine Pluripotent Stem Cells
作者: Liu, Yinan1; Li, Peng1; Liu, Kaiyu2; He, Qihua3; Han, Shuo1; Sun, Xiaofeng4; Li, Tao5; Shen, Li1
刊名: PLOS ONE
发表日期: 2014-10-14
DOI: 10.1371/journal.pone.0109588
卷: 9, 期:10
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Multidisciplinary Sciences
研究领域[WOS]: Science & Technology - Other Topics
关键词[WOS]: HUMAN SOMATIC-CELLS ; PROGENITOR CELLS ; NEURONAL DIFFERENTIATION ; WNT/BETA-CATENIN ; CARDIOMYOGENESIS ; CARDIOMYOCYTES ; PROTEIN ; MOUSE ; HEART ; STAGE
英文摘要:

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.

语种: 英语
所属项目编号: 2011CB510200 ; 31101057 ; 81303004 ; LY14C120001
项目资助者: National Basic Research Program of China (973 program) ; National Natural Science Foundation of China ; Zhejiang Provincial Natural Science Foundation
WOS记录号: WOS:000343662500056
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/62917
Appears in Collections:基础医学院_细胞生物学系_期刊论文

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作者单位: 1.Peking Univ, Sch Basic Med Sci, Dept Cell Biol, Stem Cell Res Ctr, Beijing 100871, Peoples R China
2.Peking Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Beijing 100871, Peoples R China
3.Peking Univ, Sch Basic Med Sci, Ctr Med & Hlth Anal, Beijing 100871, Peoples R China
4.Hunan Univ Chinese Med, Inst Chinese Med, Dept Histol & Embryol, Changsha, Hunan, Peoples R China
5.Zhejiang Normal Univ, Coll Chem & Life Sci, Dept Biol, Jinhua, Zhejiang, Peoples R China

Recommended Citation:
Liu, Yinan,Li, Peng,Liu, Kaiyu,et al. Timely Inhibition of Notch Signaling by DAPT Promotes Cardiac Differentiation of Murine Pluripotent Stem Cells[J]. PLOS ONE,2014,9(10).
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