This human heart tissue model, developed in Nathaniel Huebsch’s lab at WashU, allows researchers to investigate how protein aggregation disrupts heart muscle contraction and calcium handling, while providing a platform to test potential therapies for inherited and acquired heart diseases. The image shows healthy cells (left) and cells carrying the mutation (right), associated with desmin-related cardiomyopathy.
Image Credit: Huebsch lab
Scientific Frontline: Extended "At a Glance" Summary: Human Model of Desmin-Related Cardiomyopathy (DRM)
The Core Concept: Researchers at Washington University in St. Louis have engineered the first human model of desmin-related cardiomyopathy (DRM), a familial heart disease caused by protein misfolding. Utilizing induced pluripotent stem cells, the micro-engineered tissues mirror the precise concentration of human proteins, avoiding the massive overexpression required in prior animal models.
Key Distinction/Mechanism: Unlike standard laboratory cell cultures grown on flat surfaces, this model subjects human cardiomyocytes to mechanical tugging forces that mimic a real heart's resistive load. This essential mechanical stress causes the cells to properly express and organize desmin, allowing researchers to accurately observe how the mutant αB-crystallin chaperone protein aggregates, forms toxic clumps, and drags other essential proteins with it.
Major Frameworks/Components:
- Induced Pluripotent Stem Cells (iPSCs): Genetically edited human cells used to generate cardiomyocytes expressing the mutant αB-crystallin.
- Micro-engineered Heart Tissues: Miniature models specifically engineered to recreate the physical loads and mechanical forces of a beating human heart.
- Protein Quality-Control Machinery: The cellular systems regulating the intermediate filament protein desmin and its folding chaperone, which become impaired and drive toxic aggregation in DRM.
Branches of Science: Biomedical Engineering, Cellular Biology, Molecular Genetics, Cardiology, and Stem Cell Biology.
Future Application: This physiologically accurate model provides a scalable platform to test targeted therapies for DRM and other inherited or acquired cardiomyopathies, shifting treatment from generic heart failure medications to disease-specific interventions.
Why It Matters: Inherited cardiomyopathies are the leading cause of heart failure in young adults, and DRM currently lacks targeted therapies. By accurately modeling how toxic protein aggregates disrupt cellular function, researchers can now study the pathogenesis of the disease in a highly translational human system.
Inherited cardiomyopathies—diseases of the heart muscle that impair the heart's ability to pump blood to the rest of the body—are the leading cause of heart failure in young adults. Desmin-related cardiomyopathy (DRM) is one such familial disease that affects approximately 1 in 2,000 individuals worldwide. No disease-specific therapies exist for DRM, with patients receiving only generic heart failure medications.
DRM is caused by mutations in the genes for desmin—a muscle-specific intermediate filament protein—or its protein-folding chaperone, αB-crystallin (CRYAB). These mutations are thought to cause desmin to misfold and form toxic clumps inside heart muscle cells.
Severe or fatal variations of this disease have been difficult to study, in part because existing mouse models of the disorder require the massive overexpression of mutant CRYAB. Because toxic protein aggregation is driven by molecular interactions, artificially elevated protein concentrations inherently increase the probability of non-physiological binding events, confounding observations of actual pathogenesis.
Now, the first human model of CRYAB-linked DRM has been developed by researchers at Washington University in St. Louis, using micro-engineered tissues and induced pluripotent stem cells that express mutant CRYAB at a concentration closely mirroring actual levels in the human body.
“Up until now, progress has been hindered by reliance on experimental models with uncertain translational value,” said Nathaniel Huebsch, an associate professor of biomedical engineering at WashU McKelvey Engineering. “A human experimental system with physiologically relevant mutant protein expression has been a critical missing tool for understanding DRM pathogenesis and developing targeted therapies.”
In a study published in Science Advances, Huebsch and an all-WashU research team describe the engineered tissue they developed and report on their findings regarding the role of impaired protein quality-control machinery in cardiomyopathy, as well as the implications for potential treatments.
“This is a disease where desmin is aggregated and mislocalized. But the cardiomyocytes that you make in the lab from the human stem cells really don’t express this,” Huebsch said. Working collaboratively with researchers in the laboratory of Abhinav Diwan at WashU Medicine, Huebsch’s graduate student Yasaman Kargar Gaz Kooh, first author of the study, found a way around this limitation. Other key McKelvey Engineering contributors included Guy Genin, Anastasia Khokhlova, and Jonathan Silva.
Kargar used human induced pluripotent stem cells (iPSCs) that had their genomes edited to express the mutant version of CRYAB, and then used cardiomyocytes from these iPSCs to create miniaturized engineered heart tissues. One of the features of the engineered heart tissues is that cardiomyocytes within these tissues experience mechanical tugging forces and must tug against a resistive load, mimicking the physiological hemodynamics and resistive loads of an intact human heart.
The mechanical forces within the engineered heart tissues turned out to be essential. Unlike heart muscle cells grown on flat surfaces in a lab dish, cells in these miniature tissues produced desmin and organized it much like they would in a real human heart. This allowed the researchers to recreate important features of the disease that are difficult to observe in traditional laboratory models.
“In our engineered tissue, perhaps because of the mechanical forces on the cells in the tissue, the cardiomyocytes do express that desmin, and we could start to learn about how the CRYAB mutation caused it to aggregate protein,” Huebsch said.
“We were able to look at healthy cells to see what the protein expression was, and where it was distributed. It goes to the Z-disc of the cardiomyocyte,” Kargar said. “Then, in the cells that have the mutation that causes the disease, we saw that it was a bit more aggregated. It was in clumps where, presumably, not only is it not having its intended function, but it may even be pulling other proteins with it.”
Funding: A.D. was supported by grants from the National Institutes of Health (HL107594) and the Department of Veterans Affairs (I01BX005065 and I01BX005981). D.R.R. is supported by grants from the National Institutes of Health (T32 HL007081 and 1K08HL163469). N.H. and G.M.G. were supported by grants from National Institutes of Health (HL159094 and GM163062). N.H. was supported by National Science Foundation CAREER (2338931). J.R.S. was supported by the American Heart Association (Established Investigator Award 960621). G.R. and H.-Y.C.C. were supported by McDonnell Academy Fellowship. J.S.P. was supported by T32GM007200. N.H., G.M.G., and G.R. were supported in part by the NSF through the NSF Science and Technology Center for Engineering Mechanobiology, grant CMMI 1548571. H.-Y.C.C. was also supported by Taiwan MOE Fellowship.
Published in journal: Science Advances
Title: Mechanical forces enable human stem cell modeling of protein aggregation cardiomyopathy
Authors: Yasaman Kargar Gaz Kooh, Bahareh Bahmani, Chen Zhao, Ganesh Malayath, Anastasia Khokhlova, Leah Hayem, Hertier Umuragwa, Hanxun Jin, Ghiska Ramahdita, Xiangjun Peng, Huanzhu Jiang, Javier Santiago Perez, Hsin-Yi Cindy Chou, Jonathan R. Silva, Xiucui Ma, Guy M. Genin, David R. Rawnsley, Abhinav Diwan, and Nathaniel Huebsch
Source/Credit: Washington University in St. Louis | Talia Ogliore
Edited by: Scientific Frontline
Reference Number: cbio111226_01
