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.

doi:10.64898/2026.02.04.702388

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bioRxiv · 10.64898/2026.02.04.702388

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

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Abstract

Fibro-adipogenic progenitors (FAPs) in skeletal muscle have been implicated in type 2 diabetes (T2D), yet their heterogeneity and context-dependent regulation remain poorly understood. Here, we establish induced pluripotent stem cell (iPSC)-derived FAPs as a model of primary FAPs by leveraging a unique resource: iPSC lines and skeletal muscle biopsies obtained from 34 individuals, a subset of 30 profiled using single-nucleus multiomics. Donor-matched comparisons reveal iPSC-FAPs recapitulate the transcriptome, epigenome, and subtype composition of primary FAPs. Using single-nucleus multiomics, we show that high-insulin exposure drives iPSC-FAPs toward an adipogenic fate - and this adipogenic subtype is enriched for T2D GWAS signals, an enrichment undetectable at baseline. 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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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.. 2026-02-06. Donor-matched iPSC model reveals context-dependent T2D genetic signals in fibro-adipogenic progenitors. https://doi.org/10.64898/2026.02.04.702388

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