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

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 ranging from rapid improvements within weeks to no clinical benefit, suggesting additional mechanisms beyond its anti-proliferative and pro-apoptotic effects. Using patient-specific induced pluripotent stem cell-derived smooth muscle cells (iSMCs) with BMPR2 extracellular- or kinase-domain mutations, we reproduced 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 demonstrated its inhibition by sotatercept. Beyond its established effects, sotatercept rapidly reduced contractility, collagen-integrin mechanotransduction and TGFbeta receptor expression, disrupting a pathological positive feedback loop, reflected by lower levels of circulating TGFbeta1 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.