WashU researchers build first human stem-cell model of CRYAB-linked desmin cardiomyopathy
Washington University researchers grew engineered heart tissue from iPSC with the CRYAB-R120G mutation; the in vitro model reproduces desmin aggregation and impaired calcium handling.
Researchers at Washington University in St. Louis have developed the first human model of desmin-related cardiomyopathy (DRM) linked to the CRYAB-R120G mutation, according to a study published Nov. 11 in Science Advances. The model uses induced pluripotent stem cells (iPSC) that express the mutant protein at near-endogenous levels, and miniature engineered heart tissues made from their cardiomyocytes science.org
Science Advancesscience.orgOpen source ↗. The team was led by Nathaniel Huebsch, associate professor of biomedical engineering; the first author is Yasaman Kargar Gaz Kooh.
Inherited cardiomyopathies are the leading cause of heart failure in young adults. DRM affects approximately 1 in 2,000 people worldwide, and no disease-specific therapies exist: patients receive only generic heart failure medicines. The disease is caused by mutations in desmin or in its chaperone αB-crystallin (CRYAB), which compromise protein quality control and lead to toxic aggregates that destroy the contractile machinery of cardiomyocytes.
Why a physiological model was missing
R120G is one of the deadliest DRM mutations, yet it lacked a genetically matched preclinical model. Existing mouse models require massive overexpression of mutant CRYAB, which raises questions about physiological relevance, since aggregates form partly through protein interactions that depend on concentration.
According to Huebsch, cardiomyocytes made from stem cells in a dish largely do not express desmin. In the engineered tissues, cells pull against a resistive load, as in a real heart. The authors report that three-dimensional mechanical loading, but not fatty acid–based metabolic maturation media, was essential for desmin expression science.org
Science Advancesscience.orgOpen source ↗. In mutant tissues, desmin was more aggregated and formed clumps.
Calcium handling and itacitinib
The authors found that contractile deficits are associated with impaired calcium handling, pointing to electromechanical uncoupling in DRM. They did not consider the extent of desmin aggregation alone sufficient to explain the reduced contraction.
The team also tested itacitinib, a Janus kinase 1 inhibitor. Earlier work on rat cardiomyocytes in a dish had shown that inhibiting the JAK-STAT pathway cleared desmin aggregates. In the engineered tissues, itacitinib partially rescued contractility. A low dose helped mutant cells contract better, especially at higher frequency, but never to the level of healthy controls; a high dose was toxic to both healthy and mutant tissue, Huebsch said.
The next step is to determine which calcium-handling proteins malfunction in DRM and whether they are pulled into the aggregates. Abhinav Diwan of WashU Medicine, a co-author, noted that his laboratory has previously observed desmin mislocalized to aggregates in the failing heart after myocardial infarction.
