Innovative approach to cellular reprogramming: Heart scar turned into working muscle!

Cell reprogramming is a major interest in the lab of Dr.
Todd Rosengart, a professor of cardiac and vascular disease at Baylor College of Medicine and the Texas Heart Institute, whose research focuses on finding innovative treatments for heart failure
.

"Heart failure remains the leading cause of death from heart disease," Rosengart said
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"With nearly 5 million Americans at risk of developing advanced congestive heart failure, heart transplantation or mechanical circulatory support implants are currently the only options for patients with end-stage heart disease

After a heart attack, the dead part of the heart muscle doesn't regenerate new heart tissue; it's replaced by a scar that doesn't help the heart beat
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"The idea behind cellular reorganization is to direct the heart to heal itself by inducing the transformation of scar tissue, which is mostly composed of fibroblasts, into functional heart muscle," Rosengart said

Researchers have successfully reprogrammed fibroblasts in small animals to become heart muscle, dramatically improving heart function
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The challenge is how to apply the technology to human cells -- human fibroblasts are more resistant to reprogramming

"While human fibroblasts resist being reprogrammed, endothelial cells in blood vessels are known to be more resilient -- they have the ability to naturally transdifferentiate, or turn into other cells," said co-first author Megumi Mathison, PhD, associate professor of surgery at Baylor University.

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This gave us the idea to use endothelial cell plasticity to improve the efficiency of reprogramming

The researchers' idea was to first induce the fibroblasts to transform into an endothelial cell-like state, and then treat these cells with their reprogramming cocktail to induce them to become cardiomyocytes
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Their expectation was that conversion to endothelial-like cells, a cell type more easily reprogrammed than fibroblasts, would facilitate the expected conversion to heart muscle

"We were pleased to see that our method significantly improved the reprogramming efficiency of human and rat fibroblasts," Mathison said
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"Previously, the efficiency of inducing cardiomyocytes directly from fibroblasts was only 3%

The researchers' results in a rat model showing that their new strategy can restore large scar tissue to working muscle supports their continued research to bring this procedure to the clinic
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"While more research is needed, we expect this new approach could be part of the next generation of biological therapies," Rosengart said.

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This work is closely related to Baylor College of Medicine's important role in the history of artificial hearts and heart transplantation, pioneered by Dr.

Michael E.

"Years ago, Dr.
Cooley said to me that the next step was surgery to help heart failure patients, 'Todd, you have to do something dramatic
.
' To me, cellular reorganization is the 21st century's answer to that requirement," Rosengart said
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Megumi Mathison, Deepthi Sanagasetti, Vivek P.
Singh, Aarthi Pugazenthi, Jaya Pratap Pinnamaneni, Christopher T.
Ryan, Jianchang Yang, Todd K.
Rosengart.
Fibroblast transition to an endothelial “trans” state improves cell reprogramming efficiency .
Scientific Reports , 2021 ; 11 (1) DOI: 10.
1038/s41598-021-02056-x