ELABELA (ELA, Apela, Toddler) is a peptide that in humans is encoded by the APELA gene. Elabela is one of two endogenous for the G-protein-coupled Apelin receptor.
Ela is secreted by certain cell types including human embryonic stem cells.
Discovery
Elabela is a
micropeptide that was identified in 2013 by Professor
Bruno Reversade team.
Biosynthesis
Elabela gene encodes a pre-proprotein of 54 amino acids, with a
signal peptide in the
N-terminus region. After translocation into the endoplasmic reticulum and cleavage of the signal peptide, the proprotein of 32 amino acids may generate several active fragments.
Physiological functions
The sites of
Apelin receptor receptor expression are linked to the different functions played by Elabela in the organism. Despite that, Elabela is capable of signaling independently of
Apelin receptor in human embryonic stem cells
and certain cancer cell lines including OVISE.
Embryonic pluripotency
The Elabela protein is synthesized, processed and secreted by undifferentiated human embryonic stem cells
but not mouse embryonic stem cells. In humans it is under the direct regulation of POU5F1 (a.k.a. OCT4) and NANOG.
Through autocrine and paracrine signalling, endogenous Elabela entrains the PI3K/AKT/mTOR pathway to maintain pluripotency and self-renewal.
Vascular
Elabela is expressed by midline tissues (such as
Notochord in
zebrafish and
neural tube in mammals) during
organogenesis.
There it serves as a chemoattractant to expressing Apelin receptor at their cell surface.
Cardiac
The ELABELA -APLNR signaling axis is required for formation of the coronary vessels of the heart in mice through the sinus venosus progenitors.
Pre-eclampsia
ELA is a secreted into the
bloodstream by the developing
placenta.
Pregnancy mice lacking Ela,
exhibit
pre-eclampsia-like symptoms, characterized by
proteinuria and gestational hypertension.
Infusion of exogenous ELA normalizes blood pressure and prevents intrauterine growth retardation in pups born to Ela Knockout mouse mothers. ELA increases the invasiveness of trophoblast-like cells, suggesting that it may enhance placental development to prevent eclampsia.
Therapeutics
Several mimetics of ELA have been developed for
therapeutic purposes.
Amgen has created a camel
antibody and a
small molecule agonist capable of mimicking the function of ELA towards it cognate receptor APLNR.
The latter has entered phase 1 clinical trials for heart failure and acute kidney disease. Bristol Myers Squibb has also created its own small molecule agonist of APLNR.
An opinion published in the Lancet in 2019 suggested that ELABELA could be used to treat intrauterine growth restriction and maternal morbidity linked to eclampsia.
