Apical-basal polarity drives pancreatic alpha/beta cell fate allocation

ABSTRACT: Fate commitment is a sum of unique intrinsic properties and extrinsic cues received by a progenitor/stem cell. The knowledge of intrinsic properties, such as transcription, is extensive, whereas much less is known about how they are regulated by extrinsic cues, such as cell-cell and cell-extracellular matrix (ECM) interactions. We demonstrated that differential cell-cell adhesion controls the fate of multipotent pancreatic progenitors by dictating their migration to the tip and trunk niches where they are exposed to specific fate-inducing cues. Within the trunk each Neurogenin 3+ (Neurog3+) endocrine progenitor can give rise to all five pancreatic islet hormone-producing endocrine cells. Forced exiting of Neurog3+ from the polarize luminal epithelium through conditional ablation of p120ctn or Ecad in Neurog3+ cells shift their differentiation towards alpha cells at the expense of beta cells. Based on these findings we hypothesized that cell adhesion and cell polarity might be linked to the fate decision of Neurog3+ cells into the alpha and beta cell lineages. Here, we show pancreatic endocrine progenitor cell-cell adhesion is linked to apical-basal polarity and cell fate, and disruption of apical-basal polarity in the developing mouse pancreas alters endocrine cell specification. Futhermore, apical-basally polarized human endocrine progenitors are primed to become beta cells. Finally, single-cell RNA sequencing reveals beta-like transcriptional signatures and differentiation propensities in polarized endocrine progenitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE224286 | GEO | 2025/01/01

REPOSITORIES: GEO