title: ELABELA Is an Endogenous Growth Factor that Sustains hESC Self-Renewal via the PI3K/AKT Pathway.
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.
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648. Electronic address: lena.ho@reversade.com.
authors.forename: Lena
authors.initials: L
authors.lastname: Ho
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648.
authors.forename: Shawn Y X
authors.initials: SY
authors.lastname: Tan
authors.affiliation: Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673.
authors.forename: Sheena
authors.initials: S
authors.lastname: Wee
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648.
authors.forename: Sam J C
authors.initials: SJ
authors.lastname: Tan
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648.
authors.forename: Navin B
authors.initials: NB
authors.lastname: Ramakrishna
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648.
authors.forename: Serene C
authors.initials: SC
authors.lastname: Chng
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Nama
authors.forename: Iwona
authors.initials: I
authors.lastname: Szczerbinska
authors.affiliation: Genome Institute of Singapore, A(∗)STAR, Singapore 138672.
authors.forename: Iwona
authors.initials: I
authors.lastname: Sczerbinska
authors.affiliation: Genome Institute of Singapore, A(∗)STAR, Singapore 138672.
authors.forename: Yun-Shen
authors.initials: YS
authors.lastname: Chan
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648.
authors.forename: Stuart
authors.initials: S
authors.lastname: Avery
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Tsuneyoshi
authors.affiliation: Genome Institute of Singapore, A(∗)STAR, Singapore 138672.
authors.forename: Huck Hui
authors.initials: HH
authors.lastname: Ng
authors.affiliation: Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673.
authors.forename: Jayantha
authors.initials: J
authors.lastname: Gunaratne
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648.
authors.forename: N Ray
authors.initials: NR
authors.lastname: Dunn
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648; Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673. Electronic address: bruno@reversade.com.
authors.forename: Bruno
authors.initials: B
authors.lastname: Reversade
mesh_terms: D057134:Antibodies, Neutralizing; D000075244:Apelin Receptors; D002454:Cell Differentiation; D002460:Cell Line; D000066673:Cell Self Renewal; D004707:Endoderm / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019899:Paracrine Communication; D036361:Peptide Hormones / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D040901:Proteomics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C000601133:APELA protein, human; C104575:APLNR protein, human; D057134:Antibodies, Neutralizing; D000075244:Apelin Receptors; D047908:Intracellular Signaling Peptides and Proteins; D036361:Peptide Hormones; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt