Adventitial fibroblasts direct smooth muscle cell-state transition in pulmonary vascular disease

Crnkovic, S.; Thekkekara Puthenparampil, H.; Mulch, S.; Biasin, V.; Wilhelm, J.; Bartkuhn, M.; Bonyadi Rad, E.; Wawrzen, A.; Matzer, I.; Mitra, A.; Leib, R. D.; Nagy, B. M.; Sahu-Osen, A.; Valzano, F.; Bordag, N.; Evermann, M.; Hoetzenecker, K.; Olschewski, A.; Ljubojevic-Holzer, S.; Wygrecka, M.; Stenmark, K.; Marsh, L. M.; de Jesus Perez, V.; Kwapiszewska, G.

doi:10.1101/2024.05.15.594343

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bioRxiv · 10.1101/2024.05.15.594343

Adventitial fibroblasts direct smooth muscle cell-state transition in pulmonary vascular disease

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Abstract

Pulmonary vascular remodeling is a progressive pathological process characterized by functional alterations within pulmonary artery smooth muscle cells (PASMC) and adventitial fibroblasts (PAAF). Mechanisms driving the transition to a diseased phenotype remain elusive. Utilizing a combination of transcriptomic and proteomic profiling, along with phenotyping of source-matched cells from healthy controls and individuals with idiopathic pulmonary arterial hypertension (IPAH), our investigation uncovered that while PASMC and PAAF retained their original cellular identities, they acquired distinct disease-associated states. Though both cell types exhibited reduced mitochondrial content and hyperpolarization, IPAH-PASMC displayed heightened glycosaminoglycan production and downregulation of contractile machinery, contrasting a hyperproliferative phenotype of IPAH-PAAF. We investigated the involvement of cellular crosstalk in regulating cell state dynamics and identified pentraxin-3 and hepatocyte growth factor as potential modulators of PASMC phenotypic transition orchestrated by PAAF. Our findings contribute to a deeper understanding of pulmonary vascular mesenchyme dynamics in disease pathogenesis.

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Crnkovic, S., Thekkekara Puthenparampil, H., Mulch, S., Biasin, V., Wilhelm, J., Bartkuhn, M., Bonyadi Rad, E., Wawrzen, A., Matzer, I., Mitra, A., Leib, R. D., Nagy, B. M., Sahu-Osen, A., Valzano, F., Bordag, N., Evermann, M., Hoetzenecker, K., Olschewski, A., Ljubojevic-Holzer, S., Wygrecka, M., Stenmark, K., Marsh, L. M., de Jesus Perez, V., Kwapiszewska, G.. 2024-05-15. Adventitial fibroblasts direct smooth muscle cell-state transition in pulmonary vascular disease. https://doi.org/10.1101/2024.05.15.594343

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