Regulatory T-cells are required for neonatal heart regeneration

Abstract

Previous work has elegantly demonstrated that, unlike adult mammalian heart, the neonatal heart is able to regenerate after injury from postnatal day (P) 1 to 7. Recently, macrophages are found to be required in the repair process as depletion of which abolishes endogenous regenerative capability of the neonatal heart. Nevertheless, whether innate immunity alone is sufficient for neonatal heart regeneration is obscure. source of chemokines and cytokines that attract monocytes and macrophages previously known to drive neonatal heart regeneration. Furthermore, Treg directly promote proliferation of both mouse and human cardiomyocytes in a paracrine manner. Our findings uncover an unappreciated mechanism in neonatal heart regeneration; and offer new avenues for developing novel therapeutics targeting Treg-mediated heart regeneration.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

Immune responses in cardiac repair and regeneration: a comparative point of view

“…In addition, Tregs are indispensable for heart regeneration in neonatal mice, potentially by promoting monocyte/macrophage recruitment as well as CM proliferation (Fig. 4 ) [ 60 ] (a preprint article on biorxiv without peer-review). These data support an active role of Tregs in cardiac regeneration through immune modulation and the secretion of Neuregulin [ 46 ].…”

Emerging Roles for Immune Cells and MicroRNAs in Modulating the Response to Cardiac Injury

“…Over the past four years, much attention has been given to the immune response that immediately follows cardiac injury [10,20,22,25,26,44,45,46,47,48,49,50,51,52,53,54,55,56]. From these investigations, it is becoming clear that immune cells can greatly influence the course of the core cardiac repair program, controlling the balance between pro-fibrosis and pro-regeneration.…”

“…Macrophages and regulatory T cells (Tregs) are two prominent immune cells that have emerged as central players during heart regeneration. Functional studies from numerous groups have shown CM proliferation is suppressed under conditions of cell depletion [49,53,55]. However, the mechanism of action exerted on CMs and the potential influence on other immune cells are outstanding questions within the cardiac regeneration discipline.…”

“…By far, the most provocative role of Tregs lies within their compelling ability to stimulate injury-induced CM proliferation [49,53,55]. Unlike macrophages, this function has been shown to occur in vivo in the zebrafish [49], neonatal mouse [53] and adult mouse [55] as well as in human CMs co-cultured with Treg cells [53]. Currently, the only discrepancy between these three reports lies in regard to which Treg secreted factor(s) is/are responsible for stimulating CM proliferation.…”

“…By contrast, both Li et al [53] and Hui et al [49] were able to identify a single, yet different (amphiregulin, Areg [53]; neuroregulin-1, Nrg1 [49]) Treg cytokine that was able to stimulate heart regeneration. Since both of these cytokines are ligands for receptors in the erbB family [65], it is possible that the same downstream transduction cascade is being activated in neonatal mice with Areg [53] and in zebrafish with Nrg1 [49]. It is intriguing to postulate that these two cytokines may be interchangeable, as Nrg1 has been shown to induce CM proliferation in adult [66] and neonatal mice [67].…”