Resolving human α versus β cell fate allocation for the generation of stem cell-derived islets.

Authors

Melis Akgün Canan, Corinna Cozzitorto, Michael Sterr, Lama Saber, Eunike S A Setyono, Alessandro Dema, Kei Kozawa, Xianming Wang, Juliane Merl-Pham, Tobias Greisle, Ingo Burtscher, Heiko Lickert

Published in

Nature communications. Volume 17. Issue 1. Jul 09, 2026. Epub Jul 09, 2026.

Abstract

Stem cell-derived glucagon-(α) and insulin-producing (β) cells allow to engineer in vitro biomimetics of islet of Langerhans, the micro-organ controlling glycemia; however, a knowledge gap in the mechanism by which human stem cell-derived α and β cells are specified persists. Mouse studies postulated that Aristaless Related homeobox (Arx) and Paired box 4 (Pax4) transcription factors cross-inhibit each other in endocrine progenitors to promote α/β fate allocation, respectively. To test this model in human, we combine lineage labelling with single-cell multiomic analysis in our newly generated ARX^CFP/CFP; PAX4^{mCherry/mCherry} knock-in induced pluripotent stem cell reporter line. Lineage tracing, proteomic and gene regulatory network analysis and potency assays reveal a human specific regulation of α/β cell fate allocation. Pharmacological perturbations previously proposed to trigger α-to-β transdifferentiation or identified by our gene regulatory network lead to enhanced endocrine induction and directed α/β cell fate. Studying mechanisms of endocrinogenesis and fate segregation enables the engineering of islets in vitro, and has broader implications for cell-replacement therapy, disease modelling and drug screening.

PMID:
42426000
Bibliographic data and abstract were imported from PubMed on 10 Jul 2026.

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