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During a heart attack, millions of heart cells (cardiomyocytes) die from lack of oxygen. Unfortunately, these losses are irreversible, as these cells do not have the opportunity to regenerate. Depending on the severity of this degradation, the risk of heart failure and subsequent cardiac disorders can be very high. However, researchers have found an innovative way to repair and regenerate damaged cells.
If the heart has lost too many cardiomyocytes, it becomes exhausted and no longer performs (or poorly) its pumping function: this is heart failure. However, there is currently no drug that can restore heart function; transplantation remains the only option, but the low availability of donor hearts and the risk of rejection limit its widespread use. Therefore, for decades, scientists have been trying to find a way to regenerate heart cells.
Several teams rely on the use of stem cells, which could differentiate into cardiomyocytes. But there are problems with this approach: the use of embryonic stem cells and induced pluripotent stem cells is notably associated with a risk of teratoma (a type of tumor) formation. A team from the University of Houston focused on serum response factor (SRF), which plays an important role in cell cycle regulation by controlling the transcription of many genes.
A state close to that of stem cells
The heart is the first functional organ to develop during embryogenesis, and SFR is required for the formation of sarcomeres, the basic myofibril units of heart muscle, and the first heartbeat.
The researchers generated a series of mutated SRF proteins, which allow the reintegration of adult myocytes into the cell cycle. ” What we’re trying to do is dedifferentiate cardiomyocytes to a more stem cell-like state, so they can regenerate and proliferate. says Siyu Xiao, of the Department of Biology at the University of Houston. To deliver these transcription factors to heart cells, the team used synthetic mRNA, the same technology used for COVID-19 vaccines, which involves tricking cellular ribosomes into making certain proteins.
One of these mutated proteins, considered the most powerful, has been named STEMIN. Tested in cultured rat myocytes, STEMIN synthetic messenger RNA promoted partial reprogramming to a stem-like state and caused cardiomyocyte dedifferentiation. Another mutated SRF protein, called YAP5SA, directs a myriad of growth factors to proliferate dedifferentiated myocytes.
The team injected STEMIN and YAP5SA mRNA, individually and then in combination, directly into the left ventricles of living adult mice that had suffered a myocardial infarction. The objective is to check if this “treatment” would allow myocytes to be reprogrammed so that they enter the cell cycle and therefore repair damaged hearts. ” The results were impressive. said Robert Schwartz, who co-led the study with Xiao.
Hearts mended in a day
The combination of the two mRNAs has been shown to be particularly effective in restoring cardiac function, much more so than each mRNA taken individually. After injection of these transcription factors into mouse hearts, myocyte nuclei replicated at least 15 times (and even more than 17 times) in 24 hours! ” The lab found that cardiac myocytes multiplied rapidly within a day, while hearts repaired themselves over the next month to return to near-normal cardiac pumping function, with little scarring. Schwartz says.
” STEMIN and YAP5SA promoted cardiomyocyte proliferation by inhibiting SRF-dependent cardiomyocyte differentiation, bringing cardiomyocytes to a more primitive stage to promote cell replication the researchers summarize in The Journal of Cardiovascular Aging. This unprecedented approach has not only made it possible to repair heart muscle cells in mice, but also to regenerate them after a heart attack. ” Nobody has been able to do it to this point and we think it could become a possible treatment for humans. », emphasizes Schwartz.
An added advantage of using synthetic mRNA as a delivery vehicle, according to Xiao, is that it goes away on its own within days, unlike viral delivery. Indeed, gene therapies delivered to cells by viral vectors pose several biosafety issues, as they cannot be easily stopped. ” Adenovirus supply of stem cell factors is initially curative to regenerate cardiac function, but in the long term it causes cardiac radomyosarcomas. says the team.
Note that this mRNA-based gene delivery method also allows combinations of genes with different ratios to be delivered, allowing treatment to be tailored for each patient based on disease progression.