iPSC modeling of pulmonary arterial hypertension to uncover pathomechanisms and unrecognized modes of action of sotatercept

Schmidt, A.; czichon, L.; Malhofer, L.; Bartsch, G.; Ploetner, C.; Wang, Y.; Voss, C.; Kuleshova, A. E.; Kohrn, T.; Baldauf, J.; Weiss, A.; Schermuly, R.; Ruhparwar, A.; Kamp, J.-C.; Hoeper, M.; Martin, U.; Olmer, R.

doi:10.64898/2026.03.12.711267

bioRxiv · 10.64898/2026.03.12.711267

iPSC modeling of pulmonary arterial hypertension to uncover pathomechanisms and unrecognized modes of action of sotatercept

Schmidt, A.·czichon, L.·Malhofer, L.·Bartsch, G.·Ploetner, C.·Wang, Y.·Voss, C.·Kuleshova, A. E.·Kohrn, T.·Baldauf, J.·Weiss, A.·Schermuly, R.·Ruhparwar, A.·Kamp, J.-C.·Hoeper, M.·Martin, U.·Olmer, R.

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Abstract

Pulmonary arterial hypertension (PAH) is a potentially fatal disease characterized by obliterative remodeling of distal pulmonary arteries, commonly associated with bone morphogenetic receptor type 2 (BMPR2) gene mutations. In patients with PAH, sotatercept, an activin signaling inhibitor, improves hemodynamics and outcomes, but clinical responses vary and sometimes occur within weeks, suggesting additional mechanisms beyond its anti-proliferative, pro-apoptotic and anti-remodeling effects. Using patient-specific induced pluripotent stem cell-derived smooth muscle cells (iSMCs) with BMPR2 extracellular- or kinase-domain mutations, we were able to reproduce Activin A-driven PAH traits, including hyperproliferation, reduced apoptosis, enhanced contraction and excessive matrix production. We identified smooth muscle cell-to-myofibroblast transition as a previously unknown contributor to pulmonary vascular remodeling and demonstrate that it is blocked by sotatercept. Beyond its established effects, sotatercept rapidly reduced contractility, collagen-integrin mechanotransduction and TGF{beta} receptor expression, disrupting a pathological positive feedback loop, reflected by lower levels of circulating TGF{beta}1 in patients on sotatercept. Taken together, our patient-derived iSMC platform links mutation-dependent mechanisms of pulmonary vascular remodeling to variable drug responsiveness and reveals previously unrecognized, potentially rapid-acting modes of sotatercept in PAH. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/711267v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@18d5e53org.highwire.dtl.DTLVardef@2bc80dorg.highwire.dtl.DTLVardef@5ace98org.highwire.dtl.DTLVardef@1b16171_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Schmidt, A., czichon, L., Malhofer, L., Bartsch, G., Ploetner, C., Wang, Y., Voss, C., Kuleshova, A. E., Kohrn, T., Baldauf, J., Weiss, A., Schermuly, R., Ruhparwar, A., Kamp, J.-C., Hoeper, M., Martin, U., Olmer, R.. 2026-03-13. iPSC modeling of pulmonary arterial hypertension to uncover pathomechanisms and unrecognized modes of action of sotatercept. https://doi.org/10.64898/2026.03.12.711267

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