SPREDs (Sprouty Related Proteins with EVH1 Domain) promote self‐renewal and inhibit mesodermal differentiation in murine embryonic stem cells
SPREDs (Sprouty Related Proteins with EVH1 Domain) promote self‐renewal and inhibit mesodermal differentiation in murine embryonic stem cells
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DOI：
10.1002/dvdy.24261
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发表时间：
2015-04
影响因子：
2.5
通讯作者：
Bastian Mühl;J. Hägele;A. Tasdogan;Paraskevi Loula;K. Schuh;K. Bundschu
中科院分区：
文献类型：
--
作者：
Bastian Mühl;J. Hägele;A. Tasdogan;Paraskevi Loula;K. Schuh;K. Bundschu
背景资料：多能性、自我更新和分化是胚胎干细胞（ES）的特殊功能，从而为再生医学提供了有价值的前景。发育过程需要一个微调的组织，主要由众所周知的JAK/STAT，PI 3 K/AKT和ERK/MAPK途径调节。SPRED（Sprouty related proteins with EVH 1 domain）是ERK/MAPK信号通路的抑制剂，但其在胚胎干细胞和早期分化中的功能尚不清楚。结果如下：我们产生SPRED 1和SPRED 2过表达和SPRED 2敲除小鼠ES细胞，以分析SPRED蛋白在ES细胞和早期分化过程中的功能。SPRED的过表达显着增加小鼠ES细胞的自我更新和克隆形成性，而SPRED 2的缺乏会减少增殖并增加细胞凋亡。在胚状体的早期分化过程中，SPRED促进多能状态并抑制分化，从而中胚层分化为心肌细胞被显著延迟和抑制。LIF和生长因子刺激显示SPRED抑制小鼠ES细胞中的ERK/MAPK活化。然而，未检测到SPRED蛋白对LIF诱导的JAK/STAT 3或PI 3 K/AKT信号通路的激活的影响。结论：我们发现SPRED通过选择性抑制多能细胞中的ERK/MAPK信号通路促进小鼠ES细胞的自我更新并抑制中胚层分化。发展动力学244：591-606，2015年。© 2015威利期刊公司.
Background: Pluripotency, self‐renewal, and differentiation are special features of embryonic stem (ES) cells, thereby providing valuable perspectives in regenerative medicine. Developmental processes require a fine‐tuned organization, mainly regulated by the well‐known JAK/STAT, PI3K/AKT, and ERK/MAPK pathways. SPREDs (Sprouty related proteins with EVH1 domain) were discovered as inhibitors of the ERK/MAPK signaling pathway, whereas nothing was known about their functions in ES cells and during early differentiation, so far. Results: We generated SPRED1 and SPRED2 overexpressing and SPRED2 knockout murine ES cells to analyze the functions of SPRED proteins in ES cells and during early differentiation. Overexpression of SPREDs increases significantly the self‐renewal and clonogenicity of murine ES cells, whereas lack of SPRED2 reduces proliferation and increases apoptosis. During early differentiation in embryoid bodies, SPREDs promote the pluripotent state and inhibit differentiation whereby mesodermal differentiation into cardiomyocytes is considerably delayed and inhibited. LIF‐ and growth factor‐stimulation revealed that SPREDs inhibit ERK/MAPK activation in murine ES cells. However, no effects were detectable on LIF‐induced activation of the JAK/STAT3, or PI3K/AKT signaling pathway by SPRED proteins. Conclusions: We show that SPREDs promote self‐renewal and inhibit mesodermal differentiation of murine ES cells by selective suppression of the ERK/MAPK signaling pathway in pluripotent cells. Developmental Dynamics 244:591–606, 2015. © 2015 Wiley Periodicals, Inc.