Summary: Oxytocin, a hormone commonly associated with social bonding and affection, may play a direct role in repairing heart damage after a heart attack. New research shows oxytocin can activate epicardial cells—stem-like cells from the heart’s outer layer—causing them to migrate into the heart muscle and differentiate into cardiomyocytes, the contracting cells responsible for heartbeats. These findings point to potential strategies for promoting heart regeneration after cardiac injury.
Source: Frontiers (summary of research published in Frontiers in Cell and Developmental Biology)
The neurohormone oxytocin is widely known for supporting social bonds and positive emotional states, but it also regulates physiological functions such as lactation, uterine contractions, sperm transport, and testosterone production. Recent experiments in zebrafish and human cell cultures reveal an additional role: oxytocin stimulates epicardial cells to produce progenitors that rebuild damaged heart tissue.
Researchers at Michigan State University demonstrate that oxytocin prompts epicardial cells to undergo reprogramming into epicardium-derived progenitor cells (EpiPCs). These progenitors migrate into the myocardium and differentiate into cardiomyocytes, vascular cells, and other cardiac cell types needed to replace tissue lost after injury. The discovery highlights a brain-to-heart signaling mechanism that could be harnessed to enhance heart regeneration in humans.
“We show that oxytocin, a neuropeptide often called the ‘love hormone,’ activates heart repair mechanisms in injured zebrafish hearts and in human cell models,” said Dr. Aitor Aguirre, assistant professor of biomedical engineering at Michigan State University and senior author of the study. “This opens the door to potential new therapies aimed at regenerating heart tissue after damage.”
Epicardial-derived progenitors can replace lost cardiomyocytes
Cardiomyocytes, the heart’s contractile cells, are highly specialized and do not readily self-replicate following a heart attack, leading to permanent loss of functional tissue. However, the epicardium—the outer mesothelial layer of the heart—contains cells capable of reactivating developmental programs to form EpiPCs. These multipotent progenitors can differentiate into several cardiac lineages, including cardiomyocytes and vascular cells, offering a route to tissue repair.
In mammals this epicardial response is typically limited and inefficient, but the zebrafish provides an instructive model because of its remarkable regenerative capacity. Zebrafish can fully regenerate large portions of their heart after injury, relying both on proliferation of existing cardiomyocytes and on epicardium-derived progenitors.
Zebrafish studies link oxytocin to heart regeneration
Following cardiac cryoinjury in zebrafish, the researchers observed a rapid and dramatic rise in oxytocin mRNA expression in the brain—up to twenty-fold within three days. Oxytocin produced by the central nervous system appears to travel to the heart, bind to oxytocin receptors in the epicardium, and trigger signaling cascades that expand and reprogram epicardial cells into EpiPCs. These newly formed progenitors migrate into the myocardium and differentiate into cardiomyocytes and other cardiac cell types, replacing tissue lost to injury.
Comparable effects in human cell cultures
Importantly, oxytocin produced similar effects in human cell models. In vitro experiments using human induced pluripotent stem cell–derived epicardial cells showed that oxytocin robustly stimulates epicardial activation, epithelial-to-mesenchymal transition (EMT), and proliferation—driving these cells toward an EpiPC identity. Of the neurohormones tested, oxytocin was uniquely effective, increasing EpiPC formation up to twice the basal rate and outperforming previously identified molecules used in murine models.
Genetic knockdown of the oxytocin receptor in human epicardial cultures prevented this regenerative activation, confirming the receptor-dependent mechanism. Further analysis implicated the transforming growth factor–beta (TGF-β) signaling pathway as a primary mediator of oxytocin-induced epicardial activation, consistent with TGF-β’s known roles in cell growth, differentiation, and migration.
“These results suggest oxytocin-driven epicardial activation is evolutionarily conserved and could be harnessed therapeutically,” Aguirre said. “Oxytocin is already used clinically for other indications, so repurposing or developing longer-lasting, more potent oxytocin-based drugs could be a feasible strategy for patients after cardiac injury.”
The authors emphasize that oxytocin itself is short-lived in circulation, which may limit its direct use. They recommend developing molecules with improved pharmacokinetic properties and conducting preclinical animal studies followed by clinical trials to evaluate safety and efficacy in humans.
About this cardiovascular health research news
Author: Mischa Dijkstra
Source: Frontiers (summary of research)
Contact: Mischa Dijkstra, Frontiers
Image: The image is in the public domain
Original Research: Open access. “Oxytocin promotes epicardial cell activation and heart regeneration after cardiac injury” by Aitor Aguirre et al., Frontiers in Cell and Developmental Biology.
Abstract
Oxytocin promotes epicardial cell activation and heart regeneration after cardiac injury
Cardiovascular disease is a leading cause of death worldwide, often causing massive loss of cardiac muscle cells. Over the past two decades, research showed that the epicardium contributes to heart repair by activating developmental programs and generating epicardium-derived progenitor cells (EpiPCs) that can differentiate into cardiomyocytes and vascular cells. In mammals, this response is generally insufficient for full regeneration, but it might be enhanced by targeted reprogramming factors.
This study demonstrates that oxytocin, a neuroendocrine peptide from the hypothalamus, induces epicardial proliferation, EMT, and transcriptional activity in human iPSC-derived epicardial cells in vitro. In zebrafish, oxytocin production increases after cardiac injury and drives significant epicardial activation and heart regeneration; oxytocin signaling is also essential for proper epicardium development in embryos. Chemical or genetic inhibition of oxytocin signaling impairs these processes. RNA sequencing identifies the TGF-β pathway as a key mediator of oxytocin-induced epicardial activation. These findings reveal a conserved brain-controlled mechanism for cellular reprogramming and heart regeneration with potential translational relevance for treating cardiac injuries.