The neurohormone oxytocin has a number of functions involved in pleasure and social bonding, and plays a role in both female and male reproductive functions. Now, researchers have shown that in zebrafish and human cell cultures, oxytocin has yet another, unsuspected, function: it stimulates stem cells derived from the heart’s epicardium (the outer layer) to migrate into its myocardium (middle layer) and there develop into cardiomyocytes, cardiac muscle cells. This discovery could one day be used to promote the regeneration of the human heart after a heart attack. The results are published in Frontiers in Cell and Developmental Biology.
“Here we show that oxytocin, a neuropeptide also known as the love hormone, is capable of activating heart repair mechanisms in injured hearts in zebrafish and human cell cultures, opening the door to potential new therapies for heart regeneration in humans,” said senior author Dr Aitor Aguirre, an assistant professor at Michigan State University.
Stem-like cells can replenish cardiomyocytes
Cardiomyocetes typically die off in great numbers after a heart attack. Because they are highly specialised cells, they can’t replenish themselves. But previous studies have shown that a subset of cells in the epicardium can undergo reprogramming to become stem-like cells, called Epicardium-derived Progenitor Cells (EpiPCs), which can regenerate not only cardiomyocytes, but also other types of heart cells.
“Think of the EpiPCs as the stonemasons that repaired cathedrals in Europe in the Middle Ages,” explained A/Prof Aguirre.
Unfortunately for us, the production of EpiPCs is inefficient for heart regeneration in humans under natural conditions.
Zebrafish could teach us how to regenerate hearts more efficiently
Zebrafish are famous for their extraordinary capacity for regenerating organs. They don’t suffer heart attacks, but its many predators are happy to take a bite out of any organ, including the heart – so zebrafish can regrow their heart when as much as a quarter of it has been lost. This is done partly by proliferation of cardiomyocytes, but also by EpiPCs. How the EpiPCs so efficiently repair the heart, and whether they could be boosted in humans remained a mystery.
The authors argued that this was possible.
To reach this conclusion, the authors found that in zebrafish, within three days after cryoinjury – injury due to freezing – to the heart, the expression of the messenger RNA for oxytocin increases up to 20-fold in the brain. They further showed that this oxytocin then travels to the zebrafish epicardium and binds to the oxytocin receptor, triggering a molecular cascade that stimulates local cells to expand and develop into EpiPCs. These new EpiPCs then migrate to the zebrafish myocardium to develop into cardiomyocytes, blood vessels, and other important heart cells, to replace those which had been lost.
Similar effect on human tissue cultures
Crucially, the authors showed that oxytocin has a similar effect on human tissue in vitro. Of the 15 neurohormones tested, only oxytocin stimulates cultures of human Induced Pluripotent Stem Cells (hIPSCs) to become EpiPCs, at up to twice the basal rate: a much stronger effect than other molecules previously shown to stimulate EpiPC production in mice. Conversely, genetic knock-down of the oxytocin receptor prevented the the regenerative activation of human EpiPCs in culture. The authors also showed that the link between oxytocin and the stimulation of EpiPCs is the important ‘TGF-β signaling pathway’, known to regulate the growth, differentiation, and migration of cells.
A/Prof Aguirre said: “These results show that it is likely that the stimulation by oxytocin of EpiPC production is evolutionary conserved in humans to a significant extent. Oxytocin is widely used in the clinic for other reasons, so repurposing for patients after heart damage is not a long stretch of the imagination. Even if heart regeneration is only partial, the benefits for patients could be enormous.”
A/Prof Aguirre concluded: “Next, we need to look at oxytocin in humans after cardiac injury. Oxytocin itself is short-lived in the circulation, so its effects in humans might be hindered by that. Drugs specifically designed with a longer half-life or more potency might be useful in this setting. Overall, pre-clinical trials in animals and clinical trials in humans are necessary to move forward.”
Source: Frontiers
