It wasn’t that long ago that the idea of taking, for example, a skin cell and turning it into a muscle cell was unthinkable. About 10 years ago, however, groundbreaking research showed that it is indeed possible to reprogram differentiated adult cells into other types fully capable of performing new functions.
Cell reprogramming is one of the main interests of the laboratory of Dr. Todd Rosengart, chairman and professor of the Michael E. DeBakey department of surgery at Baylor College of Medicine, whose research focuses on the discovery of innovative therapeutic approaches for insufficiency. cardiac.
“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. “Almost 5 million Americans can be expected to develop advanced congestive heart failure, and heart transplantation or implantation of mechanical circulatory support are currently the only options for patients with the disease. terminally ill heart. However, these options are limited. We need to improve the way we treat this devastating disease. “
After a heart attack, the parts of the heart muscle that die do not regenerate into new heart tissue; instead, they’re replaced with a scar that doesn’t help the heart beat. “The idea behind cell reprogramming is to train the heart to heal itself by inducing scar tissue, which is mostly made up of fibroblasts, to turn into functioning heart muscle,” said Rosengart, professor of heart and vascular disease at Texas Heart. Institute.
Researchers have successfully reprogrammed fibroblasts from small animals into 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 reprogramming. In this study, Rosengart and his colleagues explored a new strategy to improve the efficiency of reprogramming human fibroblasts.
“While human fibroblasts resist reprogramming, endothelial cells, the ones that line blood vessels, are known to be more flexible – they have the ability to naturally transdifferentiate or transform into other cells,” said the co-first author, Dr Megumi Mathison, associate professor of surgery at Baylor. “This gave us the idea to use this plasticity of endothelial cells to improve the efficiency of reprogramming.”
The idea of the researchers was first to induce the transition of fibroblasts to a state similar to an endothelial cell, then to treat these cells with their reprogramming cocktail which directs them towards transformation into cardiomyocytes. It was expected that the transition to endothelial cell-like cells, a cell type more open to reprogramming than fibroblasts, would facilitate the desired change in heart muscle.
“We were delighted to see that our approach dramatically improved the efficiency of reprogramming in both human and rat fibroblasts,” said Mathison. “Previously, the direct induction of cardiomyocytes from fibroblasts was only 3% efficient. With our new approach, the efficiency was increased fivefold. It took about two to three weeks for the fibroblasts to transform. into cardiomyocytes in the lab. It was exciting to see the reprogrammed cells contract in synchrony with the surrounding cardiomyocytes. “
The researchers’ experimental results with the rat model show that their new strategy can transform large scar tissue into functional muscle, supporting their further investigation to bring this procedure to the clinic.
“Although more research is needed, we anticipate that this new approach may be part of the next generation of biologic therapies,” said Rosengart. “In a future scenario, patients with congestive heart failure would come to the cath lab, commonly referred to as the cath lab, in a hospital. The catheterization lab has diagnostic imaging equipment that helps surgeons visualize the chambers of the heart and surrounding blood vessels. when carrying out interventions. With the help of this equipment, the surgeon would inject the factors promoting the transition of fibroblasts to endothelial cells and then to cardiomyocytes directly into the heart. Follow-ups would make it possible to monitor the progress of the intervention.
This work is closely related to the prominent role that Baylor College of Medicine played in the history of the artificial heart and heart transplants initiated by Dr Michael E. DeBakey and Dr Denton A. Cooley in the 1950s and 1960s. .
“Years ago, Dr. Cooley told me, regarding the next procedures needed to help people with heart failure, ‘Todd, you have to do something dramatic.’ For me, cell reprogramming is a 21st century at this request, ”said Rosengart.
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).