ELABELA Is an Endogenous Growth Factor that Sustains hESC Self-Renewal via the PI3K/AKT Pathway
ELABELA Is an Endogenous Growth Factor that Sustains hESC Self-Renewal via the PI3K/AKT Pathway
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DOI：
10.1016/j.stem.2015.08.010
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发表时间：
2015-10-01
期刊：
影响因子：
23.9
通讯作者：
Reversade, Bruno
中科院分区：
文献类型：
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作者：
Ho, Lena;Tan, Shawn Y. X.;Reversade, Bruno
ELABELA（ELA）是一种心脏发育所需的肽类激素，通过Apelin受体（APLNR，APJ）发出信号。ELA也由不表达APLNR的人胚胎干细胞（hESC）大量分泌。在这里，我们表明，ELA信号在旁分泌的方式在hESC维持自我更新。CRISPR/Cas9介导的缺失、shRNA或中和抗体对ELA的抑制导致hESC生长减少、细胞死亡和多能性丧失。对ELA脉冲的hESC的整体磷酸化蛋白质组学和转录组学分析表明，它激活细胞存活所需的PI 3 K/AKT/mTORC 1信号传导。ELA促进hESC细胞周期进程和蛋白质翻译，并阻断应激诱导的凋亡。胰岛素和ELA在hESC培养基中具有部分重叠的功能，但只有ELA可以增强TGF β途径以使hESC向内胚层谱系致敏。我们提出，ELA，通过替代细胞表面受体，是一种内源性分泌的生长因子在人类胚胎和人胚胎干细胞，促进生长和多能性。
ELABELA (ELA) is a peptide hormone required for heart development that signals via the Apelin Receptor (APLNR, APJ). ELA is also abundantly secreted by human embryonic stem cells (hESCs), which do not express APLNR. Here we show that ELA signals in a paracrine fashion in hESCs to maintain self-renewal. ELA inhibition by CRISPR/Cas9-mediated deletion, shRNA, or neutralizing antibodies causes reduced hESC growth, cell death, and loss of pluri-potency. Global phosphoproteomic and transcriptomic analyses of ELA-pulsed hESCs show that it activates PI3K/AKT/mTORC1 signaling required for cell survival. ELA promotes hESC cell-cycle progression and protein translation and blocks stress-induced apoptosis. INSULIN and ELA have partially overlapping functions in hESC medium, but only ELA can potentiate the TGF beta pathway to prime hESCs toward the endoderm lineage. We propose that ELA, acting through an alternate cell-surface receptor, is an endogenous secreted growth factor in human embryos and hESCs that promotes growth and pluripotency.