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Tiemann, U.* ; Tian, C. ; Hermann, F.* ; Proks, M.* ; Skovgaard, E.* ; Kulik, I. ; Di, Y. ; Sedzinski, J.* ; Semb, H.

Pancreatic alpha and beta cell fate choice is directed by apical-basal polarity dynamics.

Dev. Cell 60, 1871-1883.e5 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
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A central question in cell and developmental biology is how extracellular cues control the differentiation of multipotent progenitors in a dynamically changing niche. Here, we identify apical-basal polarity as the main regulator of the differentiation of multipotent pancreatic Neurogenin3+ endocrine progenitors (EPs) into the beta or alpha cell fates. We show that human EPs dynamically change their apical-basal polarity status. Whereas polarized EPs are predisposed to differentiate into beta cells rather than alpha cells, inhibiting apical-basal polarity selectively suppresses beta cell differentiation. Single-cell RNA sequencing and complementary mechanistic data demonstrate that apical-basal polarity in human EPs promotes beta cell specification via cyclic AMP (cAMP)/PKA-cAMP response element binding protein (CREB)-EGR1-mediated inhibition of ARX expression, while reduced cAMP levels in non-polarized human EPs maintain expression of ARX, leading to alpha cell differentiation. These findings identify the apical-basal polarity status of multipotent EPs as a critical epithelial feature that determines their fate into the alpha or beta cell lineages.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Apical-basal Polarity ; Camp ; Multipotent Pancreatic Endocrine Progenitors ; Pancreas ; Pancreatic Alpha Cells ; Pancreatic Beta Cells; In-vitro; Cadherin; Progenitors; Trophectoderm; Maintenance; Neurogenin3; Generation; Expression; Distinct; Lineage
Language english
Publication Year 2025
HGF-reported in Year 2025
ISSN (print) / ISBN 1534-5807
e-ISSN 1878-1551
Journal Developmental Cell
Quellenangaben Volume: 60, Issue: 13, Pages: 1871-1883.e5 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Transl. Stem Cell Research (ITS)
POF-Topic(s) 30201 - Metabolic Health
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-506800-001
Grants Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW) at the University of Copenhagen (NNF )
Deutsche Forschungsgemeinschaft (DFG)
Helmholtz Zentrum Munchen
Novo Nordisk Foundation Center for Stem Cell Biology (DanStem) at the University of Copenhagen (NNF)
European Union
DOI 10.1016/j.devcel.2025.02.008
WOS ID 001532712700007
Scopus ID 105009286088
PubMed ID 40056911
Erfassungsdatum 2025-05-06
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