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Akgün, M. ; Cozzitorto, C. ; Sterr, M. ; Saber, L. ; Setyono, E.S.A. ; Wang, X. ; Merl-Pham, J. ; Greisle, T. ; Burtscher, I. ; Lickert, H.

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

Nat. Commun. 17:6050 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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 ARXCFP/CFP; PAX4mCherry/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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Cell ; Stem Cell ; Cell Biology ; Cell Fate Determination ; Islet ; Computational Biology ; Biology ; Chemistry ; Biotechnology ; Genetics ; Gene ; Insulin ; Transcription Factor; Pancreatic Progenitors; Efficient Generation; In-vitro; Differentiation; Expression; Pax4; Maturation; Promotes; Genes; Foxa2
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 17, Issue: 1, Pages: , Article Number: 6050 Supplement: ,
Publisher Springer
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Regeneration Research (IDR)
CF Metabolomics & Proteomics (CF-MPC)
Grants EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)