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


Date:
January 24, 2022
Source:
Osaka University
Summary:
Researchers have found that induced pluripotent stem cell--derived
cardiomyocytes from a patient with arrhythmogenic cardiomyopathy
recapitulate the reduced contractility and impaired desmosome
assembly associated with this disease, providing a rapid and
convenient platform for developing new treatments such as gene
replacement therapy.



FULL STORY ==========================================================================
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 PKP2play 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 PKP2expression
based on how many mutated or intact copies of the gene were present.

"The cells with two mutated copies of PKP2clearly 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 PKP2is the most common gene associated with arrhythmogenic cardiomyopathy, and that PKP2mutations 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.

========================================================================== Story Source: Materials provided by Osaka_University. Note: Content may
be edited for style and length.


========================================================================== Journal Reference:
1. Hiroyuki Inoue, Satoki Nakamura, Shuichiro Higo, Mikio Shiba,
Yasuaki
Kohama, Takumi Kondo, Satoshi Kameda, Tomoka Tabata, Shota Okuno,
Yoshihiko Ikeda, Junjun Li, Li Liu, Satoru Yamazaki, Maki Takeda,
Emiko Ito, Seiji Takashima, Shigeru Miyagawa, Yoshiki Sawa, Shungo
Hikoso, Yasushi Sakata. Modeling reduced contractility and impaired
desmosome assembly due to plakophilin-2 deficiency using isogenic
iPS cell-derived cardiomyocytes. Stem Cell Reports, 2022; DOI:
10.1016/ j.stemcr.2021.12.016 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220124103920.htm

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