Insulin inhibits cardiac mesoderm, not mesendoderm, formation during cardiac differentiation of human pluripotent stem cells and modulation of canonical Wnt signaling can rescue this inhibition.
Insulin inhibits cardiac mesoderm, not mesendoderm, formation during cardiac differentiation of human pluripotent stem cells and modulation of canonical Wnt signaling can rescue this inhibition.
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DOI：
10.1002/stem.1289
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发表时间：
2013-03
期刊：
影响因子：
--
通讯作者：
Palecek SP
中科院分区：
文献类型：
--
作者：
Lian X;Zhang J;Zhu K;Kamp TJ;Palecek SP
人类心脏发育的调节信号层次的研究受到缺乏模型系统的限制，该模型系统可以重现人类胚胎发生期间发生的精确发育事件。人多能干细胞（hPSC）技术和强大的心脏分化方法的出现提供了一个独特的机会，以监测心脏诱导的整个过程中在体外。在这里，我们发现，在使用TGFβ超家族配体产生心肌细胞的单层分化方案中，胰岛素信号传导的阶段特异性激活强烈抑制了心脏分化。然而，在采用经典Wnt信号传导的小分子调节剂的规定方案中，胰岛素没有抑制心肌细胞分化。通过检查胰岛素抑制心肌细胞分化的背景，我们确定胰岛素的抑制作用需要Wnt/β-catenin信号传导，并且在心脏中胚层（Nkx2.5+）阶段，通过抑制Wnt/β-catenin来挽救由胰岛素暴露引起的心肌细胞分化缺陷。因此，胰岛素和Wnt/β-catenin信号传导途径作为网络协调影响hPSC向心肌细胞的分化，其中Wnt/β-catenin途径对胰岛素途径占主导地位。我们的研究有助于了解人类心肌细胞分化的调控层次，并对人类心脏发育建模具有一定的意义。
The study of the regulatory signaling hierarchies of human heart development is limited by a lack of model systems that can reproduce the precise developmental events that occur during human embryogenesis. The advent of human pluripotent stem cell (hPSC) technology and robust cardiac differentiation methods affords a unique opportunity to monitor the full course of cardiac induction in vitro. Here we show that stage-specific activation of insulin signaling strongly inhibited cardiac differentiation during a monolayer-based differentiation protocol that used TGFβ superfamily ligands to generate cardiomyocytes. However, insulin did not repress cardiomyocyte differentiation in a defined protocol that employed small molecule regulators of canonical Wnt signaling. By examining the context of insulin inhibition of cardiomyocyte differentiation, we determined that the inhibitory effects by insulin required Wnt/β-catenin signaling and that the cardiomyocyte differentiation defect resulting from insulin exposure was rescued by inhibition of Wnt/β-catenin during the cardiac mesoderm (Nkx2.5+) stage. Thus, insulin and Wnt/β-catenin signaling pathways, as a network, coordinate to influence hPSC differentiation to cardiomyocytes, with the Wnt/β-catenin pathway dominant to the insulin pathway. Our study contributes to the understanding of the regulatory hierarchies of human cardiomyocyte differentiation and has implications for modeling human heart development.
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基因纯化的人诱导多能干细胞衍生的心肌细胞单层的同步电压和钙图谱。
影响因子：
20.1
作者：
Lee P;Klos M;Bollensdorff C;Hou L;Ewart P;Kamp TJ;Zhang J;Bizy A;Guerrero-Serna G;Kohl P;Jalife J;Herron TJ
通讯作者：
Herron TJ
影响因子：
5
作者：
McDevitt, TC;Laflamme, MA;Murry, CE
通讯作者：
Murry, CE
影响因子：
5.2
作者：
McLean, Amanda B.;D'Amour, Kevin A.;Dalton, Stephen
通讯作者：
Dalton, Stephen
影响因子：
48
作者：
Elliott, David A.;Braam, Stefan R.;Stanley, Edouard G.
通讯作者：
Stanley, Edouard G.
DOI：
10.1073/pnas.0905245106
发表时间：
2009-09-29
影响因子：
11.1
作者：
Meyer, Jason S.;Shearer, Rebecca L.;Gamm, David M.
通讯作者：
Gamm, David M.