Mechanical forces enable human stem cell modeling of protein aggregation cardiomyopathy.

Human induced pluripotent stem cell–derived microengineered heart tissues expressing CRYAB-R120G at near-endogenous levels show contractile deficits linked to impaired calcium handling.

• Why it matters: Desmin-related cardiomyopathy from CRYAB mutations lacks a genetically matched preclinical model, limiting evaluation of mechanisms and therapies under physiologic expression.
• What they did: The team engineered human iPSCs to express CRYAB-R120G and tested maturation conditions, finding 3D mechanical loading is essential for Desmin expression and aggregation. They then measured calcium handling and contractility in microengineered heart tissues and tested itacitinib, a Janus kinase 1 inhibitor.
• The result: Contractile deficits are associated with impaired calcium handling, consistent with electromechanical uncoupling, and itacitinib partially rescued contractility, supporting this therapeutic approach in the human model.

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