A Micro-Engineered Heart Tissue Model of Desmin-related Cardiomyopathy Caused by Mutant αB Crystallin

Area of Science:

• Cardiology
• Genetics
• Cell Biology

Background:

• Protein quality control (PQC) is crucial for cardiomyocyte function.
• Mutations in alpha crystallin B chain (CRYAB), like R120G, impair chaperone activity, causing protein aggregation and Desmin-related cardiomyopathy (DRM).
• Previous models required CRYAB overexpression, limiting translational relevance.

Purpose of the Study:

• To establish the first genome-edited induced pluripotent stem cell (hiPSC) model of CRYAB-linked DRM expressing mutant CRYAB at near-endogenous levels.
• To characterize disease mechanisms in a human-relevant model.
• To identify potential therapeutic targets for DRM.

Main Methods:

• Genome editing of hiPSCs to introduce the CRYAB R120G mutation.
• Generation of micro-engineered heart tissues (μHT) from mutant and isogenic control hiPSC-derived cardiomyocytes.
• Assessment of CRYAB and Desmin aggregation, contractile function, calcium handling, and PQC pathway activity.
• Pharmacological testing of JAK1 inhibition (Itacitinib).

Main Results:

• The hiPSC-derived μHT model recapitulated key DRM hallmarks, including protein aggregation and contractile dysfunction.
• Mutant CRYAB expression led to impaired calcium-contraction coupling, worsening deficits at higher pacing rates.
• JAK1 inhibition partially restored contractile function at higher frequencies.

Conclusions:

• The developed hiPSC-derived μHT platform provides a translatable model for studying proteotoxic cardiomyopathies like DRM.
• JAK1 inhibition represents a promising therapeutic strategy for CRYAB-linked DRM.
• This platform facilitates mechanistic studies and drug screening for cardiomyopathies.