Work

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

Year: 2025

Type: article

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. • Multipotent endocrine progenitors (EPs) dynamically change their polarity status • Apical-basal polarity of EPs dictates their fate toward alpha and beta cells • Polarity increases cAMP, leading to beta cell birth via reduced ARX expression • In non-polarized EPs, ARX expression is maintained, leading to alpha cell birth Tiemann and Tian et al. discover that multipotent pancreatic endocrine progenitors (EPs) differentiation is dictated by apical-basal polarity. In polarized EPs, cAMP increases via the cAMP/PKA-CREB-EGR1 pathway to inhibit ARX and promote beta cell birth, while alpha cells arise from non-polarized EPs, where the absence of cAMP elevation maintains ARX expression.

Source: Developmental Cell

DOI: 10.1016/j.devcel.2025.02.008