Vcam1+ Fibro-adipogenic Progenitors Mark Fatty Infiltration in Chronic Limb Threatening Ischemia

Dai, Q.; Wan, C.; Xu, Y.; Fei, K.; Olivere, L. A.; Garrett, B.; Akers, L.; Peters, D.; Otto, J. C.; Kontos, C. D.; Ji, Z.; Diao, Y.; Southerland, K. W.

doi:10.1101/2024.07.08.602430

bioRxiv · 10.1101/2024.07.08.602430

Vcam1+ Fibro-adipogenic Progenitors Mark Fatty Infiltration in Chronic Limb Threatening Ischemia

Dai, Q.·Wan, C.·Xu, Y.·Fei, K.·Olivere, L. A.·Garrett, B.·Akers, L.·Peters, D.·Otto, J. C.·Kontos, C. D.·Ji, Z.·Diao, Y.·Southerland, K. W.

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Abstract

Skeletal muscle health and function is a critical determinant of clinical outcomes in patients with peripheral arterial disease (PAD). Herein, we identify fatty infiltration, the ectopic deposition of adipocytes in skeletal muscle, as a histological hallmark of end-stage PAD, also known as chronic limb threatening ischemia (CLTI). Leveraging single cell transcriptome mapping in mouse models of PAD, we identify a pro-adipogenic mesenchymal stromal cell population marked by expression of Vcam1 (termed Vcam1+ FAPs) that expands in the ischemic limb. Mechanistically, we identify Sfrp1 and Nr3c1 as regulators of Vcam1+ FAP adipogenic differentiation. Loss of Sfrp1 and Nr3c1 impair Vcam1+ FAP differentiation into adipocytes in vitro. Finally, we show that Vcam1+ FAPs are enriched in human CLTI patients. Collectively, our results identify a pro-adipogenic FAP subpopulation in CLTI patients and provide a potential therapeutic target for muscle regeneration in PAD.

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Dai, Q., Wan, C., Xu, Y., Fei, K., Olivere, L. A., Garrett, B., Akers, L., Peters, D., Otto, J. C., Kontos, C. D., Ji, Z., Diao, Y., Southerland, K. W.. 2024-07-11. Vcam1+ Fibro-adipogenic Progenitors Mark Fatty Infiltration in Chronic Limb Threatening Ischemia. https://doi.org/10.1101/2024.07.08.602430

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