Comparative analyses in zebrafish and medaka after cardiac injury. At 6–48 h post cryoinjury (hpci) in zebrafish, neutrophils and macrophages have been recruited to the damaged tissue, coincident with angiogenic sprouting from existing coronaries and activation of aldh1a2 expression in both the epicardium and endocardium. In medaka, we observed reduced macrophage recruitment compared to zebrafish, but similar neutrophil recruitment. Furthermore, medaka lacks both angiogenic sprouting and induction of endocardial aldh1a2 expression during this period. At 4–7 days post cryoinjury (dpci) in zebrafish, neutrophils are gradually cleared by the increasing numbers of macrophages, while the coronary network expands to the whole injury area. Regulatory T cells (Tregs) are recruited to the damaged tissue and contribute to CM proliferation. On the other hand, in medaka, neutrophils are not cleared due to the reduced macrophage recruitment and remain in the injured area. Sporadic vessel-like structures formed by endocardial-derived cells appear at the border zone and there is no significant increase in CM proliferation. At 14–21 dpci in zebrafish, CMs actively proliferate and replace the collagen scar in a fully vascularized injured area. In medaka, vessel-like structures formed by the endocardial extensions are not stable and the collagen scar persists in the absence of replenishing CMs. Delayed macrophage recruitment in zebrafish, following pre-depletion, led to neutrophil retention, aberrant revascularization and reduced CM proliferation at 7 dpci. On the other hand, poly I:C-injected medaka exhibited enhanced macrophage recruitment and neutrophil clearance at 7 dpci, coincident with vessel formation and increased CM proliferation. How the immune response facilitates revascularization, CM dedifferentiation and proliferation, as well as scar resolution, seems to be key for a successful cardiac regeneration when comparing zebrafish to medaka
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