ELABELA Is an Endogenous Growth Factor that Sustains hESC Self-Renewal via the PI3K/AKT Pathway

Lena Ho, Shawn Y.X. Tan, Sheena Wee, Yixuan Wu, Sam J.C. Tan, Navin B. Ramakrishna, Serene C. Chng, Srikanth Nama, Iwona Szczerbinska, Yun Shen Chan, Stuart Avery, Norihiro Tsuneyoshi, Huck Hui Ng, Jayantha Gunaratne, N. Ray Dunn, Bruno Reversade

Research output: Contribution to journalArticlepeer-review

141 Scopus citations

Abstract

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 pluripotency. 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 TGFβ 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.
Original languageEnglish (US)
Pages (from-to)435-447
Number of pages13
JournalCell Stem Cell
Volume17
Issue number4
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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Generated from Scopus record by KAUST IRTS on 2023-02-15

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