Author response: Reciprocal analyses in zebrafish and medaka reveal that harnessing the immune response promotes cardiac regeneration

Abstract

Zebrafish display a distinct ability to regenerate their heart following injury. However, this ability is not shared by another teleost, the medaka. In order to identify cellular and molecular bases for this difference, we performed comparative transcriptomic analyses following cardiac cryoinjury. This comparison points to major differences in immune cell dynamics between these models. Upon closer examination, we observed delayed and reduced macrophage recruitment in medaka, along with delayed neutrophil clearance. To investigate the role of immune responses in cardiac regeneration, we delayed macrophage recruitment in zebrafish and observed compromised neovascularization, neutrophil clearance, cardiomyocyte proliferation and scar resolution. In contrast, stimulating Toll-like receptor signaling in medaka enhanced immune cell dynamics and promoted neovascularization, neutrophil clearance, cardiomyocyte proliferation and scar resolution. Altogether, these data provide further insight into the complex role of the immune response during regeneration, and serve as a platform to identify and test additional regulators of cardiac repair.

Loss ofMafbandMafdistorts myeloid cell ratios and disrupts fetal mouse testis vascularization and organogenesis

“…Interestingly, limb regeneration in adult salamanders and fin, heart, and axonal regeneration in zebrafish all require myeloid cells [86][87][88][89], and perhaps also in heart repair in mouse injury models [90]. Regeneration studies in diverse species have led to an emerging idea that a proper immune response is essential for both organ formation and regeneration [91]. Increasing evidence supports the idea that myeloid cells, such as monocytes and macrophages, play broad and evolutionarily conserved roles in organogenesis via their extensive repertoire of cellular and molecular functions, one of which is regulating vascular and tissue formation and function.…”

Ccn2a/Ctgfa is an injury-induced matricellular factor that promotes cardiac regeneration in zebrafish

“…The immune response plays a crucial role in regeneration (Hui et al, 2017;Lai et al, 2017). In mammals, immune cells express CXCR3 and preferentially help in the migration of immune cells into inflamed tissue (Torraca et al, 2015).…”

“…Adult mammalian hearts fail to regenerate after myocardial damage, typically leading to persistent scarring and reduced heart function (Engel et al, 2006;Doppler et al, 2017). In contrast, zebrafish can regenerate their injured myocardium through cardiomyocyte (CM) proliferation (Poss et al, 2002) aided by a specific immune response (Hui et al, 2017;Lai et al, 2017) and the ability to clear transient collagen deposition (Poss et al, 2002;González-Rosa et al, 2011) (Fig. 1A).…”

Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes

“…In this regard, endogenous macrophages have emerged as essential players for heart regeneration in lower vertebrates and neonatal mice. Indeed, macrophage depletion impairs myocardium regeneration following injuries, leading to scar formation in zebrafish (70) and neonatal mice (71,72). Secretion of Oncostatin M (OSM, described in the "Growth factors and cytokines" section) by macrophages/monocytes appears to be essential for cardiomyocyte proliferation during neonatal heart regeneration (73).…”