Innovative approach brings cell-reprograming therapy for heart failure
closer to reality

Date:
January 6, 2022
Source:
Baylor College of Medicine
Summary:
Researchers have developed a new cell reprogramming strategy can
change large scar tissue in rat hearts into working muscle.



FULL STORY ==========================================================================
Not too long ago the idea of taking, for instance a skin cell and
transforming it into a muscle cell was unthinkable. About 10 years ago, however, revolutionary research showed that it is indeed possible to
reprogram differentiated adult cells into other types fully capable of conducting new functions.


==========================================================================
Cell reprogramming is a main interest of the lab of Dr. Todd Rosengart,
chair and professor of the Michael E. DeBakey Department of Surgery at
Baylor College of Medicine, whose research focuses on finding innovative therapeutic approaches for heart failure.

"Heart failure remains the leading cause of death from heart disease,"
said Rosengart, DeBakey-Bard Chair in Surgery and professor of
molecular and cellular biology at Baylor. "Nearly 5 million Americans
can be expected to develop advanced congestive heart failure, and heart transplant or mechanical circulatory support implantation currently are
the only options for patients with end-stage heart disease. However, these options are limited. We need to improve how to treat this devastating condition." After a heart attack, the parts of the heart muscle that
die do not regenerate into new heart tissue; instead, they are replaced
by a scar that does not help the heart to beat. "The idea behind cell reprograming is to coach the heart to heal itself by inducing the scar
tissue, which is made mostly of fibroblasts, to change into functional
heart muscle," said Rosengart, professor of heart and vascular disease
at the Texas Heart Institute.

Researchers have succeeded at reprograming fibroblasts from small
animals to become heart muscle, with dramatic improvements in heart
function. The challenge has been to apply this technology to human cells
-- human fibroblasts are more resistant to reprograming. In this study, Rosengart and his colleagues explored a novel strategy to enhance the reprogramming efficiency of human fibroblasts.

"While human fibroblasts resist being reprogramed, endothelial cells,
those that line the blood vessels, are known to be more flexible -- they
have the capacity to naturally transdifferentiate or change into other
cells," said co- first author Dr. Megumi Mathison, associate professor
of surgery at Baylor.

"This gave us the idea of using this endothelial cell plasticity to
improve the reprograming efficiency." The researchers' idea was to first induce fibroblasts to transition into an endothelial cell-like state and
then treat these cells with their reprograming cocktail that directs them
to change into cardiomyocytes. The expectation was that transitioning
into endothelial cell-like cells, a cell type more open to reprogramming
than fibroblasts, would facilitate the desired change into heart muscle.



==========================================================================
"We were delighted to see that our approach significantly enhanced reprogramming efficiency both in human and rat fibroblasts," Mathison
said.

"Previously, inducing cardiomyocytes from fibroblasts directly was only 3% efficient. With our new approach, the efficiency increased 5 times. It
took about two to three weeks for the fibroblasts to transition into cardiomyocytes in the lab. It was exciting to see the reprogrammed
cells contracting in synchrony with surrounding cardiomyocytes."
The researchers' experimental results with the rat model show that their
new strategy can revert large scar tissue into working muscle, supporting continuing their investigations to bring this procedure to the clinic.

"Although more research is needed, we anticipate that this novel
approach can become part of the next generation of biological therapies," Rosengart said.

"In a future scenario, patients with congestive heart failure would
come to the catheterization laboratory, commonly referred to as the
cath lab, in a hospital. The cath lab has diagnostic imaging equipment
that helps surgeons visualize the chambers of the heart and surrounding
blood vessels as they conduct procedures. Assisted by this equipment,
the surgeon would inject the factors that promote the transition from fibroblasts to endothelial cells and then to cardiomyocytes directly
into the heart. Follow ups would monitor the progress of the procedure."
This work strongly ties into the prominent role Baylor College of Medicine
has played in the history of the artificial heart and heart transplants pioneered by Dr. Michael E. DeBakey and Dr. Denton A. Cooley in the
1950s and 60s.

"Years ago, Dr. Cooley said to me, regarding the next procedures needed
to help people with heart failure, 'Todd, you got to do something that
is dramatic.' For me, cell reprograming is a 21st century answer to
this request," Rosengart said.

This study was funded by the National Heart, Lung and Blood Institute (R01HL121294?01A1, R01HL 152280, 5T32HL139430), the Baylor College of
Medicine Cytometry and Cell Sorting Core (National Institutes of Health
grants P30AI036211, P30CA125123, S10RR024574; the National Institute of
Allergy and Infectious Diseases grant AI036211), and the Baylor College
of Medicine Integral Microscopy Core (NIH DK56338, CPRIT RP150578,
and RP170719).

========================================================================== Story Source: Materials provided by Baylor_College_of_Medicine. Original written by Ana Mari'a Rodri'guez, Ph.D.. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. 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 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220106133300.htm

--- up 4 weeks, 5 days, 7 hours, 13 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)