Researchers at the
University of Houston are reporting a first-of-its-kind technology that not
only repairs heart muscle cells in mice but also regenerates them following a
heart attack, or myocardial infarction as its medically known.
Published in the Journal
of Cardiovascular Aging, the
groundbreaking finding has the potential to become a powerful clinical strategy
for treating heart disease in humans, according to Robert Schwartz, Hugh Roy
and Lillie Cranz Cullen Distinguished Professor of biology and biochemistry at
the UH College of Natural Sciences and Mathematics.
The new technology developed by the team
of researchers uses synthetic messenger ribonucleic acid (mRNA) to deliver
mutated transcription factors — proteins that control the conversion of DNA
into RNA — to mouse hearts.
“No one has been able to do this to this
extent and we think it could become a possible treatment for humans,” said
Schwartz, who led the study with recent Ph.D graduate Siyu Xiao and Dinakar
Iyer, a research assistant professor of biology and biochemistry.
Synthetic
mRNA Contributes to Stem Cell-Like Growth
The researchers demonstrated that two
mutated transcription factors, Stemin and YAP5SA, work in tandem to increase
the replication of cardiomyocytes, or heart muscle cells, isolated from mouse
hearts. These experiments were conducted in vitro on tissue culture dishes.
“What we are trying to do is
dedifferentiate the cardiomyocyte into a more stem cell-like state so that they
can regenerate and proliferate,” Xiao said.
Stemin turns on stem cell-like
properties from cardiomyocytes. Stemin’s crucial role in their experiments was
discovered by Iyer, who said the transcription factor was a “game changer.”
Meanwhile, YAP5SA works by promoting organ growth that causes the myocytes to
replicate even more.
In a separate finding published in the
same journal, the team will report that Stemin and YAP5SA repaired damaged
mouse hearts in vivo. Notably, myocyte nuclei replicated at least 15-fold in 24
hours following heart injections that delivered those transcription factors.
Bradley McConnell, professor of
pharmacology, and graduate student Emilio Lucero in the UH College of Pharmacy,
collaborated on the study by producing the infarcted adult mouse model.
“When both transcription factors were
injected into infarcted adult mouse hearts, the results were stunning,”
Schwartz said. “The lab found cardiac myocytes multiplied quickly within a day,
while hearts over the next month were repaired to near normal cardiac pumping
function with little scarring.”
An added benefit of using synthetic
mRNA, according to Xiao, is that it disappears in a few days as opposed to
viral delivery. Gene therapies delivered to cells by viral vectors raise
several biosafety concerns because they cannot be easily stopped. mRNA-based
delivery, on the other hand, turns over quickly and disappears.
A
Limited Number of Cardiomyocytes
Schwartz and Iyer worked on this study
for several years, and Xiao focused on this research throughout her doctoral
studies at UH. She graduated in fall 2020.
“I feel honored and lucky to have worked
on this,” Xiao said. “This is a huge study in heart regeneration especially
given the smart strategy of using mRNA to deliver Stemin and YAP5SA.”
The findings are especially important
because less than 1% of adult cardiac muscle cells can regenerate. “Most people
die with most of the same cardiomyocytes they had in the first month of life,”
she said. When there is a heart attack and heart muscle cells die, the
contracting ability of the heart can be lost.
Source: https://uh.edu/news-events/stories/2022-news-articles/june-2022/06162022-cardiac-cell-study.php
Journal article: https://cardiovascularaging.com/article/view/4882
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