Distinct effects of inflammation on preconditioning and regeneration of the adult zebrafish heart

Abstract

The adult heart is able to activate cardioprotective programmes and modifies its architecture in response to physiological or pathological changes. While mammalian cardiac remodelling often involves hypertrophic expansion, the adult zebrafish heart exploits hyperplastic growth. This capacity depends on the responsiveness of zebrafish cardiomyocytes to mitogenic signals throughout their entire life. Here, we have examined the role of inflammation on the stimulation of cell cycle activity in the context of heart preconditioning and regeneration. We used thoracotomy as a cardiac preconditioning model and cryoinjury as a model of cardiac infarction in the adult zebrafish. First, we performed a spatio-temporal characterization of leucocytes and cycling cardiac cells after thoracotomy. This analysis revealed a concomitance between the infiltration of inflammatory cells and the stimulation of the mitotic activity. However, decreasing the immune response using clodronate liposome injection, PLX3397 treatment or anti-inflammatory drugs surprisingly had no effect on the re-entry of cardiac cells into the cell cycle. In contrast, reducing inflammation using the same strategies after cryoinjury strongly impaired cardiac cell mitotic activity and the regenerative process. Taken together, our results show that, while the immune response is not necessary to induce cell-cycle activity in intact preconditioned hearts, inflammation is required for the regeneration of injured hearts in zebrafish.

Macrophages directly contribute collagen to scar formation during zebrafish heart regeneration and mouse heart repair

“…Recent studies have revealed that macrophages are essential players in the regeneration of the salamander limb 12 , adult zebrafish tail fin 16 and neonatal mouse heart 10 . Studies in zebrafish have also reported impaired heart regeneration upon a decreased macrophage response 11,13,15,44,45 . However, the molecular programmes deployed by macrophages to either dampen adverse effects of inflammation in an environment permissive for the positive effects of the immune response or to directly exacerbate fibrosis during wound healing remain unknown.…”

Autophagy Activation in Zebrafish Heart Regeneration

“…4). These time points were chosen according to the reported apoptosis and inflammatory cell-recruitment maxima 39,40 in the zebrafish model, where it has been described that altered presence of inflammatory cells as a result of decreased pro-inflammatory neutrophil clearance or a diminished macrophage recruitment response, have a direct repercussion in the regeneration outcome [41][42][43] . Interestingly, modulating inflammatory therapeutic strategies are being considered as an alternative option to minimize the damage upon a myocardial infarct 44,45 .…”

Zebrafish heart regeneration: 15 years of discoveries

“…Although our understanding of the role of inflammation in regeneration is still limited, several lines of evidence suggest that this early inflammatory response is essential for regeneration. Treatment with anti‐inflammatory drugs or chemical depletion of phagocytes and neutrophils impair revascularization and cardiomyocyte proliferation, leading to the accumulation of a fibrotic scar (Huang, Yang, et al., ; de Preux Charles, Bise, Baier, Marro, & Jaźwińska, ). These results are in agreement with findings from zebrafish brain regeneration, where inflammation is both necessary and sufficient to activate injury‐induced programs, including proliferation and neurogenesis (Kyritsis et al., ).…”