traitement régénération cellules cardiaques

New mRNA therapy to repair heart after heart attack

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During a heart attack, millions of heart cells (cardiomyocytes) die due to lack of oxygen. Unfortunately, these losses are irreversible, as these cells do not have the opportunity to regenerate. Depending on the severity of this deterioration, the later risk of heart failure and other heart problems can be very high. However, researchers have found an innovative way to repair and regenerate damaged cells.

If the heart loses too many heart muscle cells, it ends up exhausting and can no longer (or poorly) perform its pump function: this is heart failure. However, there is currently no drug that can restore heart function. Transplant remains the only option, but the lack of availability of donor hearts and the risk of rejection limit its widespread use. Thus, for decades, scientists have been trying to find a way to regenerate heart cells.

Several teams rely on the use of stem cells, which can be differentiated into cardiomyocytes. But this approach poses some problems: the use of embryonic stem cells and induced pluripotent stem cells is particularly associated with the risk of developing teratomas (a type of tumor). A team from the University of Houston focused on serum response factor (SRF), which plays a key role in cell cycle regulation by controlling the transcription of many genes.

A case close to that of stem cells

The heart is the first functional organ to develop during embryonic development, and the SFR is essential for the formation of sarcomas – the basic units of myofibrils in the myocardium – and the first heartbeat.

The researchers produced a series of mutant SRF proteins, which allow adult muscle cells to be reintegrated into the cell cycle. ” What we’re trying to do is de-differentiate the cardiomyocytes into a stem cell-like state, so they can regenerate and multiply. says Siu Xiao, of the University of Houston’s Department of Biology. To deliver these transcription factors into heart cells, the team used synthetic mRNA — the same technology used in COVID-19 vaccines, which involves tricking the cell’s ribosomes into producing specific proteins.

One of these mutant proteins, which is considered the most powerful, was named STEMIN. Tested in rat muscle cell cultures, the synthetic mRNA for STEMIN promoted partial reprogramming to a stem-like state and caused de-differentiation of cardiomyocytes. Another mutated SRF protein, called YAP5SA, directs a myriad of growth factors for the proliferation of undifferentiated muscle cells.

The team injected STEMIN and YAP5SA mRNA, individually and then together, directly into the left ventricles of live adult mice that had suffered myocardial infarction. The goal is to check if this ‘treatment’ will make it possible to reprogram muscle cells to enter the cell cycle and thus repair damaged hearts. ” The results were amazing said Robert Schwartz, who co-led the study with Xiao.

Hearts repaired in a day

The combination of two mRNAs has been shown to be particularly effective in restoring cardiac function – much more than each mRNA taken separately. After injecting these transcription factors into the hearts of mice, muscle cell nuclei doubled at least 15 times (and even more than 17 times) in 24 hours! ” The lab found that heart muscle cells multiply rapidly within a day, while hearts repaired over the next month to return to the heart’s near-normal pumping function, with little to no scarring. Schwartz says.

The figure shows an example of the repair He lives From the heart of an infarcted adult mouse, by injecting a mixture of STEMIN and YAP5SA mRNA. After four weeks, the severed and stained hearts show a significant reduction in the affected area. © Journal of Cardiovascular Aging

STEMIN and YAP5SA enhanced cardiomyocyte proliferation by inhibiting SRF-dependent cardiomyocyte differentiation, thus pushing cardiomyocytes to a more primitive stage to promote cell proliferation. Summarize the researchers in Journal of Cardiovascular Aging. This unprecedented approach not only made it possible to repair heart muscle cells in mice, but also to regenerate them after a heart attack. ” No one has been able to do this to this extent and we believe it could become a possible cure for humans. Schwartz confirms.

An additional advantage of using synthetic mRNA as a delivery method, according to Xiao, is that it disappears on its own within days, unlike viral delivery. Gene therapies delivered to cells by viral vectors already raise several biosafety issues, as they cannot be easily stopped. ” Delivery of stem cell factors with adenovirus is an initial treatment to regenerate cardiac function, but in the long term it causes cardiomyosarcoma. The team says.

Note that this mRNA-based gene delivery method also makes it possible to deliver groups of genes of different proportions, which makes it possible to customize treatment for each patient according to disease progression.

Source: S. Xiao et al., The Journal of Cardiovascular Aging

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