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

Article · Akgün Canan M, Cozzitorto C, Sterr M, Saber L, Setyono ESA, Dema A, Kozawa K, Wang X, Merl-Pham J, Greisle T, Burtscher I, Lickert H

- Archive id: doi:10.1038/s41467-026-75255-7
- Published: 2026-07-09
- Venue: Nature communications
- DOI: https://doi.org/10.1038/s41467-026-75255-7
- PMID: 42426000
- PMCID: PMC13351057
- Citations: 3
- Source URL: https://doi.org/10.1038/s41467-026-75255-7
- PDF: https://europepmc.org/articles/PMC13351057/pdf
- Provenance: europepmc

## 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.

_Abstract reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [Gene & Cell Therapy](https://space-kitty.com/topics/gene-cell-therapy)

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