Donor-matched iPSC model reveals context-dependent T2D genetic signals in fibro-adipogenic progenitors
Ventresca, C.; Varshney, A.; Orchard, P.; Vu, H. T. H.; Tsan, Y.-c.; Monteiro da Rocha, A.; Erdos, M. R.; Kinnunen, L.; Lakka, T. A.; Saramies, J.; Laakso, M.; Tuomilehto, J.; Mohlke, K.; Boehnke, M.; Scott, L. J.; Koistinen, H. A.; Collins, F. S.; Herron, T.; Bielas, S.; Parker, S. C. J.
Show 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-associated rs3814707 non-coding signal to LTBP3, a gene that influences FAP adipogenic differentiation. These findings reveal how disease-relevant regulatory mechanisms can be masked in unstimulated cells and establish iPSC-FAPs as a powerful platform for dissecting the state-dependent biology of complex metabolic disease.
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