A stem cell knockout village reveals lineage rewiring and a non-canonical islet cell fate in monogenic diabetes.

ABSTRACT: Genetics studies have identified a core set of regulators essential for pancreatic β cell development, many of which are mutated in monogenic diabetes. However, how these mutations alter developmental trajectories to produce pathological cell states remains elusive. Here we introduce a knockout village framework that enables longitudinal scRNA-seq profiling of 79 human pluripotent stem cell mutant lines targeting 30 developmental regulators, including 15 diabetes genes, across five islet differentiation stages. We show that loss of lineage regulators impairs β cell formation in a stage-specific manner and rewires developmental trajectories towards competing lineages. Notably, several monogenic diabetes gene mutations drive a shift from β cells to enterochromaffin (EC)-like cells, a recentl

SUBMITTER: Liu D 

PROVIDER: S-EPMC12776134 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature