December 4, 2022

CPK model of the Oxitocin molecule. Credit: CC0

The neurohormone oxytocin is known for promoting social bonds and inducing pleasurable feelings, for example through art, exercise or sex. But the hormone has many other functions, such as regulating breastfeeding and uterine contractions in women, and regulating ejaculation, sperm transport and testosterone production in men.

Now, Michigan State University researchers show that in zebrafish and human cell cultures, oxytocin has another unsuspected function: it stimulates stem cells derived from the outer layer of the heart (epicardium) to migrate to the middle layer (myocardium) and 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 were published in Frontiers in Cell and Developmental Biology.

“Here we show that oxytocin, a neuropeptide also known as the love hormone, is able to activate cardiac repair mechanisms in injured hearts in zebrafish and human cell cultures, opening the door to potential new therapies for cardiac regeneration in humans,” said Dr. . Aitor Aguirre, an assistant professor in the Department of Biomedical Engineering at Michigan State University, and the study’s senior author.

Stem-like cells can replenish cardiomyocytes

Cardiomyocytes typically die in large numbers after a heart attack. Because they are highly specialized cells, they cannot 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 other types of heart cells as well.

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“Think of the EpiPCs as the stonemasons who repaired cathedrals in Europe in the Middle Ages,” explains Aguirre.

Unfortunately for us, the production of EpiPCs under natural conditions is inefficient for heart regeneration in humans.

Zebrafish can teach us how to regenerate hearts more efficiently

Enter the Zebrafish: Famous for their extraordinary ability to regenerate organs, including the brain, retina, internal organs, bones and skin. They don’t have heart attacks, but the many predators like to take a bite out of every organ, including the heart, so zebrafish can grow their hearts when as much as a quarter of it is lost. This occurs partly through proliferation of cardiomyocytes, but also through EpiPCs. But how do zebrafish EpiPCs repair the heart so efficiently? And can we find a “magic bullet” in zebrafish that can artificially stimulate the production of EpiPCs in humans?

Yes, and this “magic bullet” appears to be oxytocin, the authors argue.

To reach this conclusion, the authors found that in zebrafish, within three days of cryoinjury — injury from frostbite — in 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 epicardium of the zebrafish and binds to the oxytocin receptor, activating a molecular cascade that stimulates local cells to expand and develop into EpiPCs. These new EpiPCs then migrate to the myocardium of the zebrafish to develop into cardiomyocytes, blood vessels and other important heart cells to replace the lost cells.

Similar effect on human tissue cultures

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Crucially, the authors demonstrated that oxytocin has a similar effect on human tissue in vitro. Oxytocin — but none of the 14 other neurohormones tested here — stimulates cultures of human induced pluripotent stem cells (hIPSCs) to become EpiPCs, at twice the basal rate: a much stronger effect than other molecules previously shown to inhibit the EpiPC. stimulate production in mice. Conversely, genetic knockdown of the oxytocin receptor prevented 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”, which is 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 highly evolutionarily conserved in humans. Oxytocin is widely used in the clinic for other reasons, so repurposing patients after cardiac injury is not an option.” long imagination. Even if heart regeneration is only partial, the benefits for patients can be enormous.”

“Next, we need to look at oxytocin in humans after heart injury. Oxytocin itself is short-lived in the circulation, so its effects in humans may be hampered by that. Drugs specifically designed with a longer half-life or greater potency may be helpful in this setting In general, preclinical animal and human clinical trials are needed to make progress,” Aguirre concluded.

Special cells contribute to regenerating the heart in zebrafish

More information:
Aaron Wasserman et al, Oxytocin promotes epicardial cell activation and cardiac regeneration after cardiac injury, Frontiers in Cell and Developmental Biology (2022). DOI: 10.3389/fcell.2022.985298