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

Patient-specific iPSC-derived smooth muscle cells with BMPR2 extracellular- or kinase-domain mutations reproduce Activin A-driven PAH traits, and sotatercept inhibits smooth muscle-to-myofibroblast transition.

• Why it matters: PAH involves distal pulmonary artery remodeling and BMPR2 mutations, yet sotatercept responses vary widely, implying mechanisms beyond its known anti-proliferative and pro-apoptotic actions.
• What they did: The study used iSMCs carrying BMPR2 extracellular- or kinase-domain mutations to model PAH traits, then tested sotatercept effects on transition, contractility, collagen-integrin mechanotransduction, and TGFbeta receptor expression.
• The result: Sotatercept rapidly reduced contractility and TGFbeta receptor expression, lowered circulating TGFbeta1 in patients, and disrupted a pathological positive feedback loop linked to remodeling.

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