News Release

My heart will go on: Patient-derived heart cells mimic disease in vitro

Researchers from Osaka University find that patient-derived cardiomyocytes carrying a mutation associated with arrhythmogenic cardiomyopathy exhibit the decreased contraction and impaired desmosome assembly seen in this disease

Peer-Reviewed Publication

Osaka University


image: Reduced contractility and impaired desmosome assembly in isogenic iPS cell-derived cardiomyocytes. view more 

Credit: © 2022 Hiroyuki Inoue et al., Modeling reduced contractility and impaired desmosome assembly due toplakophilin-2 deficiency using isogenic iPS cell-derived cardiomyocytes, Stem Cell Reports

Osaka, Japan - How can you mend a broken heart? According to researchers from Japan, in some cases gene replacement therapy just might do the trick.

In a study published in January in Stem Cell Reports, researchers from Osaka University report that heart cells from a patient with an inherited heart disease called arrhythmogenic cardiomyopathy do not contract correctly when grown in the laboratory, and that replacing the mutated gene responsible for this effect fixes this defect.

Arrhythmogenic cardiomyopathy occurs due to mutations in genes involved in desmosomes, which form ‘welds’ between cells that help them communicate and move in a coordinated way. One of these genes, PKP2, encodes a protein known as plakophilin-2 that is crucial to maintaining heart cell structure.

“Previous studies carried out in cardiomyocytes have shown that mutations in PKP2 play a pathological role in arrhythmogenic cardiomyopathy,” says lead author of the study Hiroyuki Inoue. “However, the cells used in those experiments were derived from healthy individuals and were not assessed for contractile function.”

To investigate how cells derived from patients behave in the laboratory, the researchers first took a blood sample from a young patient with arrhythmogenic cardiomyopathy, induced some of the blood cells to become stem cells, and then differentiated these stem cells into heart cells. They then modified this original batch of heart cells into three different cell lines with precisely adjusted PKP2 expression based on how many mutated or intact copies of the gene were present.

“The cells with two mutated copies of PKP2 clearly exhibited reduced contractility and impaired desmosome assembly due to plakophilin-2 deficiency,” explains Shuichiro Higo, senior author. “These effects were also observed in cells with only one mutated copy of PKP2, although they were less severe.”

Replacing the mutated PKP2 with an intact copy of the gene repaired the defects in both cell contraction and desmosome assembly, which the researchers were able to observe using a time-lapse approach and fluorescently labeled desmosomes.

“These findings suggest that our cardiomyocyte cell lines recapitulate the pathology of arrhythmogenic cardiomyopathy and provide a rapid and convenient platform for developing gene-based therapies for this disease,” says Higo.

Given that PKP2 is the most common gene associated with arrhythmogenic cardiomyopathy, and that PKP2 mutations can lead to severe disease, new therapeutic approaches could help halt disease progression. The findings from this study suggest that gene replacement therapy could be a valuable way of treating patients with this condition and the cell lines created in this study are a viable model to test new therapies for arrhythmogenic cardiomyopathy on.


The article, “Modeling reduced contractility and impaired desmosome assembly due to plakophilin-2 deficiency using isogenic iPS cell-derived cardiomyocytes,” was published in Stem Cell Reports at DOI:


About Osaka University

Osaka University was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world, being named Japan's most innovative university in 2015 (Reuters 2015 Top 100) and one of the most innovative institutions in the world in 2017 (Innovative Universities and the Nature Index Innovation 2017). Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.




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