First human model for form of inherited heart disease uses realistic levels of mutant protein

A groundbreaking development in understanding a rare form of inherited heart disease has been achieved by researchers at Washington University in St. Louis. The disease, known as Desmin-related cardiomyopathy (DRM), affects approximately 1 in 2,000 individuals worldwide and causes the heart to struggle in pumping blood due to misfolded proteins.

Traditionally, studying this disease has been challenging because existing mouse models require excessively high levels of mutant protein, which may not accurately represent the real-life situation.

Now, scientists have created the first human model of CRYAB-linked DRM, utilizing micro-engineered tissues and induced pluripotent stem cells (iPSCs) that express mutant CRYAB at levels similar to those found in humans. This significant advancement was made possible by a collaborative effort between researchers in the laboratory of Abhinav Diwan, M.D., and Nathaniel Huebsch, an associate professor of biomedical engineering at WashU McKelvey Engineering. The team's achievement has been highlighted by the Science Advances journal.

The engineered tissues were developed by first modifying human iPSCs to express the mutant version of CRYAB, followed by the creation of cardiomyocytes from these iPSCs. These cardiomyocytes were then used to construct miniature engineered heart tissues, which experienced mechanical tugging forces and had to tug against a resistive load, just like in a real heart.

This unique feature allowed the researchers to observe the cardiomyocytes' ability to organize desmin protein much like in a real human heart, a process that is difficult to replicate in traditional laboratory models.

The researchers found that cardiomyocytes in healthy tissues expressed desmin at the Z-disk of the cardiomyocyte, while those with the disease-causing mutation showed higher levels of desmin aggregation in clumps. This aggregation, which hinders the protein's intended function, could also pull other proteins with it. Additionally, Kargar's tests revealed that tissues with desmin aggregation exhibited improper calcium handling, a finding that could be crucial for understanding the immediate consequences of heart attacks, where cells experience a loss of oxygen and nutrients.