# WashU researchers build first human stem-cell model of CRYAB-linked desmin cardiomyopathy

- Published: 2026-11-13 13:35 UTC
- Section: Life & Health › Medicine
- Tags: desmin-related cardiomyopathy, CRYAB-R120G, induced pluripotent stem cells, engineered heart tissue, calcium handling, JAK1 inhibitor, protein aggregation, Science Advances, heart failure in young adults
- URL: https://realtech.media/news/rt-8bbed6740d994bb20b26680c_washu_researchers_build/

**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.**

![WashU researchers build first human stem-cell model of CRYAB-linked desmin cardiomyopathy](https://realtech.media/media/2026/11/99cfaa1929ee2ba2.png)
*newswise.com*

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 [1]. 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 [1].

## 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 [1].

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 [1]. 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 [1]. 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 [1]. 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.

## Sources

1. [Science Advances](https://doi.org/10.1126/sciadv.aee9464)
2. [newswise.com](https://www.newswise.com/articles/washu-researchers-develop-first-human-model-for-form-of-inherited-heart-disease)

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Source: RealTech, realtech.media — https://realtech.media/news/rt-8bbed6740d994bb20b26680c_washu_researchers_build/