Summary: Oxytocin, a hormone connected with bonding and love, could help to heal damage following a heart attack. Researchers found oxytocin stimulates stem cells from the heart’s outer layer and migrates into the middle layer where it develops into muscle cells that generate heart contractions. This could be used to promote the regeneration of heart cells following a heart attack.
The neurohormone oxytocin is well-known for promoting social bonds and generating pleasurable feelings, for example from art, exercise, or sex. But the hormone has many other functions, such as the regulation of lactation and uterine contractions in females, and the regulation of ejaculation, sperm transport, and testosterone production in males.
Now, researchers from Michigan State University show that in zebrafish and human cell cultures, oxytocin has yet another, unsuspected, function: it stimulates stem cells derived from the heart’s outer layer (epicardium) to migrate into its middle layer (myocardium) and there develop into cardiomyocytes, muscle cells that generate heart contractions. 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 Dr Aitor Aguirre, an assistant professor at the Department of Biomedical Engineering of Michigan State University, and the study’s senior author.
Stem-like cells can replenish cardiomyocytes
Cardiomyocetes typically die off in great numbers after a heart attack. Because they are highly specialized 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 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
Enter the zebrafish: famous for their extraordinary capacity for regenerating organs, including the brain, retina, internal organs, bone, and skin. 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. But how do the EpiPCs of zebrafish repair the heart so efficiently? And can we find a ‘magic bullet’ in zebrafish that could artificially boost the production of EpiPCs in humans?
Yes, and this ‘magic bullet’ appears to be oxytocin, argue the authors.
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. Oxytocin – but none of 14 other neurohormones tested here – 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.
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.”
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.”
Oxytocin promotes epicardial cell activation and heart regeneration after cardiac injury
Cardiovascular disease (CVD) is one of the leading causes of mortality worldwide, and frequently leads to massive heart injury and the loss of billions of cardiac muscle cells and associated vasculature.
Critical work in the last 2 decades demonstrated that these lost cells can be partially regenerated by the epicardium, the outermost mesothelial layer of the heart, in a process that highly recapitulates its role in heart development.
Upon cardiac injury, mature epicardial cells activate and undergo an epithelial-mesenchymal transition (EMT) to form epicardium-derived progenitor cells (EpiPCs), multipotent progenitors that can differentiate into several important cardiac lineages, including cardiomyocytes and vascular cells.
In mammals, this process alone is insufficient for significant regeneration, but it might be possible to prime it by administering specific reprogramming factors, leading to enhanced EpiPC function.
Here, we show that oxytocin (OXT), a hypothalamic neuroendocrine peptide, induces epicardial cell proliferation, EMT, and transcriptional activity in a model of human induced pluripotent stem cell (hiPSC)-derived epicardial cells.
In addition, we demonstrate that OXT is produced after cardiac cryoinjury in zebrafish, and that it elicits significant epicardial activation promoting heart regeneration. Oxytocin signaling is also critical for proper epicardium development in zebrafish embryos.
The above processes are significantly impaired when OXT signaling is inhibited chemically or genetically through RNA interference. RNA sequencing data suggests that the transforming growth factor beta (TGF-β) pathway is the primary mediator of OXT-induced epicardial activation.
Our research reveals for the first time an evolutionary conserved brain-controlled mechanism inducing cellular reprogramming and regeneration of the injured mammalian and zebrafish heart, a finding that could contribute to translational advances for the treatment of cardiac injuries.