Abstract
The nature of the early post-natal immune response in rodents appears to influence cardiac regeneration even though the underlying molecules remain poorly understood. Consistent with this idea, we show now significant changes in the expression of immune and cell movement gene pathways in heart samples from 1- and 7-day-old rats with ventricle resection. We then tested whether conditioned media from adult M2 anti-inflammatory macrophages target neonatal cardiac cells to a pro-regenerative like phenotype compared to the M1 pro-inflammatory macrophages. We found that M2 compared to M1 macrophage-conditioned media upregulates neonatal cardiomyocyte proliferation, suppresses myofibroblast-induced differentiation and stimulates endothelial cell tube formation. Using a cytokine array, we selected four candidate cytokine molecules uniquely expressed in M2 macrophage-conditioned media and showed that two of them (IL-4 and IL-6) induce endothelial cell proliferation whilst IL-4 promotes proliferation in neonatal cardiomyocytes and prevents myofibroblast-induced collagen type I secretion. Altogether, we provided evidence that adult M2 macrophage-conditioned media displays a paracrine beneficial pro-regenerative response in target cardiac cells and that IL-4 and IL-6 recapitulate, at least in part, these pleiotropic effects. Further characterization of macrophage immune phenotypes and their secreted molecules may give rise to novel therapeutic approaches for post-natal cardiac repair.
Highlights
The nature of the early post-natal immune response in rodents appears to influence cardiac regeneration even though the underlying molecules remain poorly understood
We observed that the inflammatory pattern of activation is different between 1-day-old and the 7-day-old resected rats and demonstrated that the adult M2 macrophage-conditioned media recapitulates the pro-regeneration effects on target cardiac cells suggesting that the quality of the inflammation may play a role
Even after an important stimulus, that is, left ventricle resection in which approximately 16% of the total heart is removed, as assessed by pre- and post-MRI, the global molecular signatures appear to be mainly correlated with the ontogeny of the organ and not with the experimental procedure, as shown by an unsupervised analysis using the primary component analysis (PCA) of the RNASeq data (Fig. 1B)
Summary
The nature of the early post-natal immune response in rodents appears to influence cardiac regeneration even though the underlying molecules remain poorly understood. The second wave of inflammation is responsible for secreting growth factors and recruiting/activating reparative cells to preserve the structural integrity of the chamber and prevent wall r upture[3,4,5,6] Leukocyte subsets such as pro- (M1) and anti-inflammatory (M2) macrophages play an important role in repairing the injured heart, and there may be differences in their profile between neonates and a dults[7,8,9,10]. We observed that the inflammatory pattern of activation is different between 1-day-old and the 7-day-old resected rats and demonstrated that the adult M2 macrophage-conditioned media recapitulates the pro-regeneration effects on target cardiac cells suggesting that the quality of the inflammation may play a role. IL-4 and IL-6 recapitulate, at least in part, these pleiotropic regenerative effects, suggesting that key inflammatory mediators display a regenerative-like response in cardiac target cells
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