Pancreatic alpha and beta cell fate choice is directed by apical-basal polarity dynamics
Tiemann U, Tian C, Hermann F, Proks M, Skovgaard E, Kulik I, Di Y, Sedzinski J, Semb H (2025)
Publication Type: Journal article
Publication year: 2025
Journal
Book Volume: 60
Pages Range: 1871-1883.e5
Journal Issue: 13
DOI: 10.1016/j.devcel.2025.02.008
Abstract
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.
Involved external institutions
Novo Nordisk Foundation / Novo Nordisk Fonden (NNF)
Denmark (DK)
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich
Germany (DE)
University of Copenhagen
Denmark (DK)
Denmark (DK)
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich
Germany (DE)
University of Copenhagen
Denmark (DK)
How to cite
APA:
Tiemann, U., Tian, C., Hermann, F., Proks, M., Skovgaard, E., Kulik, I.,... Semb, H. (2025). Pancreatic alpha and beta cell fate choice is directed by apical-basal polarity dynamics. Developmental Cell, 60(13), 1871-1883.e5. https://doi.org/10.1016/j.devcel.2025.02.008
MLA:
Tiemann, Ulf, et al. "Pancreatic alpha and beta cell fate choice is directed by apical-basal polarity dynamics." Developmental Cell 60.13 (2025): 1871-1883.e5.
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