Donor-matched iPSC model reveals context-dependent T2D genetic signals in fibro-adipogenic progenitors.

ABSTRACT: Fibro-adipogenic progenitors (FAPs) in skeletal muscle have been implicated in type 2 diabetes (T2D) risk, yet their heterogeneity and context-dependent regulation remain poorly understood. Here, we establish induced pluripotent stem cell (iPSC)-derived FAPs as a faithful model of primary FAPs by leveraging a unique resource: iPSC lines and skeletal muscle biopsies obtained from the same 30 individuals. Donor-matched comparisons reveal that iPSC-FAPs recapitulate the transcriptome, epigenome, and subtype composition of muscle tissue FAPs. Using single-nucleus multiomics, we show that high-insulin exposure drives iPSC-FAPs toward an adipogenic fate - and that this adipogenic subtype is enriched for T2D GWAS signals, an enrichment undetectable under baseline conditions. We map the T2D-associ

SUBMITTER: Ventresca C 

PROVIDER: S-EPMC12889671 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature