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学科主题基础医学
Timely Inhibition of Notch Signaling by DAPT Promotes Cardiac Differentiation of Murine Pluripotent Stem Cells
Liu, Yinan1; Li, Peng1; Liu, Kaiyu2; He, Qihua3; Han, Shuo1; Sun, Xiaofeng4; Li, Tao5; Shen, Li1
刊名PLOS ONE
2014-10-14
DOI10.1371/journal.pone.0109588
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
WOS记录号WOS:000343662500056
项目编号2011CB510200 ; 31101057 ; 81303004 ; LY14C120001
资助机构National Basic Research Program of China (973 program) ; National Natural Science Foundation of China ; Zhejiang Provincial Natural Science Foundation
引用统计
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/62917
专题北京大学基础医学院_细胞生物学系
北京大学医学部管理机构_医学部
北京大学基础医学院
北京大学精神卫生研究所_精神科
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
推荐引用方式
GB/T 7714
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).
APA Liu, Yinan.,Li, Peng.,Liu, Kaiyu.,He, Qihua.,Han, Shuo.,...&Shen, Li.(2014).Timely Inhibition of Notch Signaling by DAPT Promotes Cardiac Differentiation of Murine Pluripotent Stem Cells.PLOS ONE,9(10).
MLA Liu, Yinan,et al."Timely Inhibition of Notch Signaling by DAPT Promotes Cardiac Differentiation of Murine Pluripotent Stem Cells".PLOS ONE 9.10(2014).
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