Key result
3D mechanical loading induces desmin expression in ~30% of hiPSC-CMs, while itacitinib partially rescues contractility.
Why the study?
The CRYAB-R120G mutation in desmin-related cardiomyopathy lacked a genetically matched preclinical model, as existing mouse models require massive overexpression of mutant CRYAB with questionable physiological relevance.
Does 3D mechanical loading enable physiological modeling of CRYAB-R120G desmin-related cardiomyopathy in human iPSC-derived cardiac tissues, and does JAK1 inhibition with itacitinib rescue the resulting contractile dysfunction?
Does 3D mechanical loading enable physiological modeling of CRYAB-R120G desmin-related cardiomyopathy in human iPSC-derived cardiac tissues, and does JAK1 inhibition with itacitinib rescue the resulting contractile dysfunction?
Three-dimensional mechanical loading is essential to induce physiological Desmin expression in human stem cell-derived cardiomyocytes, enabling the first genetically matched human preclinical model of CRYAB-R120G protein aggregation cardiomyopathy and demonstrating partial functional rescue via JAK1 inhibition with itacitinib.
Answers are grounded in this paper and cite their sources.
3D hiPSC models may refine preclinical testing of desmin-related cardiomyopathy; leaves open whether JAK1 inhibition benefits patients.
Inherited cardiomyopathies are the leading cause of heart failure in young adults, with limited therapeutic options. Desmin-related cardiomyopathy (DRM), caused by mutations to cytoskeletal proteins and their chaperones, exemplifies this challenge: Here, protein quality control is compromised, leading to toxic protein aggregates that destroy cardiomyocyte contractile machinery. One of the deadliest DRM mutations in the chaperone protein αB crystallin (CRYAB-R120G) lacks a genetically matched preclinical model: Mouse models require massive overexpression of mutant CRYAB, raising questions about physiological relevance. Here, we establish a human model of CRYAB -linked DRM, using induced pluripotent stem cells expressing CRYAB-R120G at near-endogenous levels. We show that three-dimensional mechanical loading, but not fatty acid–based metabolic maturation media, is essential for expressing Desmin, whose aggregation defines DRM. Using microengineered heart tissues, we found that contractile deficits are associated with impaired calcium handling, pointing to electromechanical uncoupling in DRM. Treatment with the Janus kinase 1 inhibitor itacitinib partially rescued contractility, providing a functional validation of this emerging therapeutic strategy.
No takes yet. Share an insight, caveat, or question.
Kooh et al. (2026) studied Desmin-related cardiomyopathy (CRYAB-R120G mutation). 3D mechanical loading and itacitinib vs. 2D monolayer culture, isogenic wild-type (CRYAB-WT) controls, and vehicle control was evaluated on Desmin expression, protein aggregation, and contractile performance (contractility index and peak active force) (p=<0.0001). Three-dimensional mechanical loading induced Desmin expression in ~30% of hiPS-CMs, and 0.1 μM itacitinib partially rescued contractile deficits in CRYAB-R120G tissues at 2 Hz.
Synapse has enriched 10 related papers. Consider them for comparative context: