There’s no cure for a broken heart – or so scientists thought until recently. We’re not talking about matters of romance, but the literal organ. And the stakes could not be higher. According to the World Health Organization, heart disease is the world’s biggest killer, with heart attacks alone responsible for about 16% of all global deaths.
One of the key reasons for that is that, unlike skin or bone, the human hearts cannot repair themselves; once they’re damaged, they’re damaged. However, there’s a short period at the very start of our lives, heart tissue retains the ability to regenerate before this capacity mysteriously shuts down. For a research team led by Professor Kathy Lui Oi-lan from the Department of Chemical Pathology at The Chinese University of Hong Kong’s Faculty of Medicine (CU Medicine), that realisation was the beginning of a long journey that has recently led them to an exciting place: the discovery of exactly how the heart does so. It opens the possibility of treating heart disease by taking the heart’s dormant ability to regenerate and switching it back on.
An unexpected ally, the immune system
The secret, as so often, can be found within the human immune system. CD4+ Treg cells (full name: CD4+ FOXP3+ regulatory T-cells) are a type of white blood cells that regulate the immune system, preventing potentially dangerous excessive immune reactions, as well as reducing inflammation.
In 2018, though, the CUHK team discovered that Treg cells can also do rather more than this: in people with type 2 diabetes, they help to promote blood flow and the growth of new blood vessels. This prompted the team to wonder whether the same ability to stimulate repair could also apply in the heart. They confirmed this the following year, discovering that Tregs can indeed stimulate the repair of cardiomyocyte, a type of specialised muscle cells that make up about three-quarters of our hearts by volume. However, it hasn’t been clear precisely how they do so – until now.
The key player turns out to be a protein called MRG15 (full name: MORF-related gene 15) – which Treg cells can turn on and off. This is extremely handy, because while MRG15 is present and correct in the hearts of newborn babies, the body stops expressing it as the heart gets older.
The molecular switch: MRG15
“We adopted a comparative strategy, analysing the gene expression profiles of cardiomyocytes from neonatal hearts, which can regenerate, versus juvenile hearts, which cannot,” says Professor Lui. “During normal postnatal development, the number of functional cardiac Tregs and the expression level of MRG15 in cardiomyocytes both decline in parallel as the heart loses its regenerative capacity. Additionally, following myocardial infarction in neonatal hearts, we observed that both the cardiac Treg response and MRG15 expression in cardiomyocytes surged shortly after injury and then gradually returned to baseline. We hypothesised that MRG15 is the active epigenetic mediator—the key— through which Tregs execute their pro-regenerative function.”
In experiments on mice, the researchers tried deleting MRG15 in very young hearts, and also reactivating it in older hearts. Unsurprisingly, the former had a negative effect on heart repair – but so did removing the Treg cells. Conversely, reactivating MRG15 had a very positive effect on heart tissue’s ability to repair itself – even in the absence of Treg cells. In other words, MRG15 serves as an essential mediator for CD4+ Treg cells to function, and both are indispensable for effective cardiac repair.
“This discovery has important therapeutic implications,” notes Professor Lui. “While Tregs are a powerful endogenous trigger, broadly modulating the immune system can have widespread off-target effects, as immune cells influence many organs beyond the heart. In contrast, MRG15 represents a more precise, heart-specific target.”
The results were striking: reactivating MRG15 reduced scarred tissue in the juvenile heart from about 4% to just 0.5%, a dramatic improvement pointing to genuine regeneration rather than limited repair. The implications are profound: for the first time, scientists may be able to coax the adult heart into healing itself—challenging one of the most entrenched assumptions in cardiovascular medicine.
Towards heart-healing therapies
The next step is to translate the results into a therapeutic strategy. The goal is a therapy that can precisely target heart tissue, express MRG15 with controlled timing and dosing, and cause as few side effects as possible. The professor says the team’s priorities include developing a safe, efficient delivery system, and working out how MRG15 functions differently in infant and adult cardiomyocytes.
“Our foundational finding – that reactivating this key epigenetic regulator can re-enable cardiomyocyte proliferation in a post-neonatal heart – is highly promising. It strongly suggests that strategies aimed at delivering or reactivating MRG15 or modulating its pathway could form a viable therapeutic approach for adult heart repair,” says Professor Lui.
“Our goal is to integrate our insights to develop novel, precise therapeutic strategies that can meaningfully improve heart repair and function in patients suffering from heart failure.”
