Paracrine effect of regulatory T cells promotes cardiomyocyte proliferation during pregnancy and after myocardial infarction

Abstract

Cardiomyocyte proliferation stops at birth when the heart is no longer exposed to maternal blood and, likewise, to regulatory T cells (Tregs) that are expanded to promote maternal tolerance towards the fetus. Here, we report a role of Tregs in promoting cardiomyocyte proliferation. Treg-conditioned medium promotes cardiomyocyte proliferation, similar to the serum from pregnant animals. Proliferative cardiomyocytes are detected in the heart of pregnant mothers, and Treg depletion during pregnancy decreases both maternal and fetal cardiomyocyte proliferation. Treg depletion after myocardial infarction results in depressed cardiac function, massive inflammation, and scarce collagen deposition. In contrast, Treg injection reduces infarct size, preserves contractility, and increases the number of proliferating cardiomyocytes. The overexpression of six factors secreted by Tregs (Cst7, Tnfsf11, Il33, Fgl2, Matn2, and Igf2) reproduces the therapeutic effect. In conclusion, Tregs promote fetal and maternal cardiomyocyte proliferation in a paracrine manner and improve the outcome of myocardial infarction.

Message in a Bottle: Upgrading Cardiac Repair into Rejuvenation

“…Indeed, accumulating evidence from state-of-the-art preclinical models in rodents and lower vertebrates, like the zebrafish, suggest that signals activating cardiomyocyte proliferation elicit global activation within the myocardium, pointing at paracrine mechanisms as master drivers of endogenous tissue reactivation [76,77]. The relevance of such intercellular communication has been further confirmed by recent studies emphasising the instructing role of macrophages in driving angiogenesis during murine neonatal heart regeneration [78] and of regulatory T cells in promoting foetal and maternal cardiomyocyte proliferation during pregnancy and after myocardial infarction [79].…”

Surviving Acute Organ Failure: Cell Polyploidization and Progenitor Proliferation

“…CDK1, CDK4, cyclin B1, and cyclin D1 significantly improved heart function after acute myocardial infarction by inducing efficient division of cardiomyocytes [100]. Likewise, cardiomyocyte proliferation is promoted during pregnancy and after myocardial infarction by factors produced by T-regulatory cells, thus improving outcomes, suggesting that it could represent a potential therapeutic target [101].…”

“…Current treatments include fluid control, vasopressors, inotropic medications, antiarrhythmic drugs, or ultimately ventricular assist devices [102]. Shifting from polyploidization to proliferation can improve heart function after acute myocardial infarction in animal models suggesting this may represent a potential target for future treatments [100,101].…”

Wearable and Implantable Devices for Cardiovascular Healthcare: from Monitoring to Therapy Based on Flexible and Stretchable Electronics

“…Although cell therapies have shown improvement in left ventricular function, there is no strong evidence that the administered cells have successfully engrafted with the host myocardium . The therapeutic effect may have shown by the paracrine effect owing to the low survivability of the injected donor cells . Even if the cells have engrafted into the host myocardium, only 0.1 to 10% of the cells continue to survive for more than a few weeks .…”