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ELA – A New Member of the Pluripotency Network

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Review of “ELABELA Is an Endogenous Growth Factor that Sustains hESC Self-Renewal via the PI3K/AKT Pathway” from Cell Stem Cells by Stuart P. Atkinson

Slowly and surely, stem cell scientists are beginning to understand the molecular underpinnings of pluripotency, but now and again, a few surprises pop up! One recent unexpected finding came from the laboratory of Bruno Reversade (A∗STAR, Singapore) who, for the first time, identified a hormonal peptide necessary for the growth and self-renewal of human embryonic stem cells (hESCs). In this new study, published in Cell Stem Cell, the group shows that ELABELA (ELA) is a secreted growth factor that supports pluripotency via the activation of PI3K/AKT signaling, but it’s receptor in hESCs still remains a mystery [1].

Ho et al initially demonstrated high ELA expression and secretion in undifferentiated hESCs, followed by rapid silencing during differentiation. ELA loss (CRISPR/Cas9-mediated deletion, shRNA, or neutralizing antibodies) under self-renewing conditions, led to reduced hESC proliferation, increased apoptosis, the loss of colony formation, enhanced differentiation, and the loss of teratoma-forming ability, all suggesting that secreted ELA acts in a paracrine fashion to mediate hESC self-renewal. Indeed, treatment of primed hESCs, but not naïve hESCs, with ELA induced cell growth in a dose-dependent manner, although other more differentiated human cell types showed no response.

So how does ELA produce these effects? The study found that while ELA binds to a cell surface receptor and is subsequently internalized, hESCs do not express the known ELA receptor (APLNR), suggesting that a so-far-unidentified alternate receptor is in play. Interaction of ELA with this receptor did, however, activate pathways previously linked to the maintenance of hESC growth and self-renewal. Much like INSULIN and IGFs, ELA proved to activate the PI3K/AKT and mTORC1 pathways [2, 3], and in doing so, protected hESCs and promoted their proliferation and expansion by boosting protein translation, promoting cell cycle progression, and inhibiting stress-induced apoptosis in self-renewing hESCs. 

In a final twist, the authors also discovered that ELA also had an unexpected role in differentiation where it primed hESCs for mesendodermal differentiation functioning through the NODAL/TGF pathway. They note that this does not correlate with known functions of INSULIN, so suggesting that while they have some overlapping roles, INSULIN and ELA signaling are distinct.

While we can add ELA to the sprawling pluripotency network, further questions, as always, arise. ELA seems to acts to buffer the effects of stress in hESCs and, presumably, the cells of the human blastocysts where it is also highly expressed. But which stress signal is ELA responding to and what are the molecular underpinnings regulating its expression and secretion? Furthermore, the previously mentioned conundrum of the receptor for ELA in hESCs still requires to be solved. Lastly, the authors also note that given the potent effects of ELA in hESCs, that ELA expression may be necessary for cancer stem cell propagation, and if it is, can we effectively target ELA to inhibit tumorigenesis?

References

  1. Ho L, Tan SY, Wee S, et al. ELABELA Is an Endogenous Growth Factor that Sustains hESC Self-Renewal via the PI3K/AKT Pathway. Cell Stem Cell 2015;17:435-447.
  2. Armstrong L, Hughes O, Yung S, et al. The role of PI3K/AKT, MAPK/ERK and NFkappabeta signalling in the maintenance of human embryonic stem cell pluripotency and viability highlighted by transcriptional profiling and functional analysis. Hum Mol Genet 2006;15:1894-1913.
  3. Zhou J, Su P, Wang L, et al. mTOR supports long-term self-renewal and suppresses mesoderm and endoderm activities of human embryonic stem cells. Proc Natl Acad Sci U S A 2009;106:7840-7845.