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TMEM219 regulates the transcription factor expression and proliferation of beta cells

Authors :
Francesca D’Addio
Emma Assi
Anna Maestroni
Giada Rossi
Vera Usuelli
Adriana Petrazzuolo
Marta Nardini
Cristian Loretelli
Moufida Ben Nasr
Paolo Fiorina
Source :
Frontiers in Endocrinology, Vol 15 (2024)
Publication Year :
2024
Publisher :
Frontiers Media S.A., 2024.

Abstract

Pancreatic beta cells replenishment is considered the next therapeutic option for type 1 diabetes; while stimulating endogenous beta cells proliferation is the “holy grail” for those patients with exhausted beta cell mass. Here we are demonstrating that the pro-apoptotic receptor TMEM219 is expressed in fetal pancreas, in beta cell precursors and in in vitro embryonic-derived endocrine progenitors. TMEM219 signaling negatively regulates beta cells at early stages and induces Caspase 8-mediated cell death. Pharmacological blockade of TMEM219 further rescued beta cell precursor and proliferation markers, and decreased cell death, both in islets and in in vitro-derived endocrine progenitors, allowing for beta cell preservation. While addressing the upstream controlling TMEM219 expression, we determined the TMEM219 miRNet; indeed, one of those miRNAs, miR-129-2, is highly expressed in human islets, particularly in patients at risk or with established type 1 diabetes. miR-129-2 mimic downregulated TMEM219 expression in islets, in in vitro embryonic-derived endocrine progenitors and in highly proliferating insulinoma-derived cells. Moreover, miR-129-2 inhibitor induced a TMEM219 overexpression in insulinoma-derived cells, which restored cell proliferation and functional markers, thus acting as endogenous regulator of TMEM219 expression. The TMEM219 upstream regulator miR129-2 controls the fate of beta cell precursors and may unleash their regenerative potentials to replenish beta cells in type 1 diabetes.

Details

Language :
English
ISSN :
16642392
Volume :
15
Database :
Directory of Open Access Journals
Journal :
Frontiers in Endocrinology
Publication Type :
Academic Journal
Accession number :
edsdoj.3c19f5f129a14d3dadfdbfbfd1eeb6c7
Document Type :
article
Full Text :
https://doi.org/10.3389/fendo.2024.1306127