A team of international researchers has taken a significant step toward making heart regeneration a clinical reality, identifying a hormonal mechanism that suppresses the heart's natural ability to repair itself — and showing that blocking it with existing drugs can restore that capacity.
The study, coordinated by scholars from the University of Bologna and the IRCCS Sant'Orsola Polyclinic, was published in the journal Nature Cardiovascular Research.
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When a heart attack, myocarditis, or certain cancer treatments damage the heart, the affected cardiomyocytes — the muscle cells responsible for the heart's pumping action — are lost permanently. The body replaces them with non-contractile fibrotic tissue, which contributes directly to heart failure, a serious condition in which the heart can no longer pump sufficient blood to meet the body's needs.
The key insight driving this research is that the mammalian heart is capable of regenerating itself immediately after birth. In newborns, cardiomyocytes respond to growth factors and proteins called cytokines that stimulate cell proliferation. This ability, however, disappears rapidly in the early stages of postnatal life as heart cells mature.
The researchers set out to understand why — and specifically, whether something was actively suppressing the heart's regenerative response, not just failing to promote it.
The answer, they found, lies with glucocorticoids — steroid hormones that play an essential role in the maturation of organs after birth, but that simultaneously shut down the heart's regenerative programmes.
"We discovered that glucocorticoids significantly limit the ability of cardiomyocytes to respond to regenerative growth factors," said Gabriele D'Uva, professor at the University of Bologna's Department of Medical and Surgical Sciences and the study's lead coordinator. "In practice, they act as a hormonal brake that shuts down the heart's regenerative programmes."
Having identified glucocorticoids as the culprit, the team tested whether blocking their receptor could remove the brake on heart cell regeneration.
"We have seen that, in preclinical models, inhibiting this receptor restores the cardiomyocytes' response to growth factors, thereby stimulating heart cell proliferation even in later postnatal stages and adulthood," said Silva Da Pra, postdoctoral researcher and lead author of the study.
The approach proved particularly effective in addressing heart damage caused by anthracyclines — chemotherapy drugs that are widely used in cancer treatment but are known to be toxic to the heart.
PhD student Stefano Boriati, the study's second author, said that combining a glucocorticoid antagonist with a regenerative factor significantly reduced heart damage, preserved heart function, and promoted cardiomyocyte survival — with results that were substantially better than either treatment used alone.
D'Uva said that if the findings are validated in humans, the strategy could have a meaningful impact on the treatment of heart failure.
"Temporarily inhibiting the action of glucocorticoids through pharmacological inhibitors can substantially boost the effectiveness of growth factor-based regenerative therapies," he said.
The next phase of the research will focus on developing combined therapeutic approaches and optimising the timing and methods of intervention to maximise heart tissue regeneration in clinical settings.