Oxytocin promotes epicardial cell activation and heart regeneration after cardiac injury

Abstract

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.

Oxytocin Modulates Osteogenic Commitment in Human Adipose-Derived Stem Cells

“…It is also known that OXT promotes tissue repair and cell differentiation of stem cells [ 6 ]. Many types of research have addressed the role of OXT on cardiogenesis, which is mediated by OXTR [ 21 ]: OXT stimulates cardiac differentiation both in P19 cells [ 21 ] and in embryoid bodies obtained from mouse ESCs [ 22 ] as well as in adult murine Sca-1-positive cells that, in the adult hearts, have some characteristics of stem cells [ 23 ]; the same cardiac differentiation effect was observed in porcine BM-MSCs [ 24 ], in mouse ASCs [ 25 ], in UCB-MSCs [ 26 ], and in iPSC-derived epicardial cells [ 27 ]. OXT also stimulates the stem cell chondrogenic differentiation [ 28 ], making this molecule an interesting candidate for osteoarthritis treatment [ 29 ]: in fact, in hBM-MSCs and hASCs, OXT enhances the mRNA expression of genes involved in chondrogenesis [ 28 ].…”

Effects of oxytocin on the hair growth ability of dermal papilla cells

“…1 , 2 ). Several other cell sources, including microglia, islet cells, and cardiomyocyte, have OXTR and respond to OXT at 0–10 µM concentration 26 – 29 . Therefore, OXT treatment at different concentrations (0, 0.1, 1, and 10 µM) was administered to DP cells in 2D culture for 6 days.…”

Regeneration of the heart: from molecular mechanisms to clinical therapeutics

“…Nrg1 sustains the epicardial-mediated cardiac regeneration capacity of neonatal heart explants [ 179 ]. Oxytocin also activates epicardial cells and promotes heart regeneration after cardiac injury [ 180 ]. Daily administration of thymosin β4, a peptide known to restore vascularization of the epicardium [ 181 ], gives mice the capability of producing new cardiomyocytes and improves recovery after myocardial infarction [ 182 , 183 ].…”