Lai et al., 2018 - Immune responses in cardiac repair and regeneration: a comparative point of view. Cellular and molecular life sciences : CMLS   76(7):1365-1380 Full text @ Cell. Mol. Life Sci.

Fig. 1

Cardiac injury models. Illustration of myocardial infarction (MI), resection, cryoinjury and genetic ablation of cardiomyocytes (CMs). MI is induced by surgically ligating the left anterior descending coronary artery, leading to tissue death downstream of the ligature. Resection is used to remove part of the ventricle. Cryoinjury is used to cauterize part of the ventricle with a cryoprobe. Genetic ablation is achieved by driving CM-specific Nitroreductase (NTR) expression, which in turn converts a prodrug into a cytotoxic product leading to CM death; alternatively, CM-specific expression of the Diphtheria toxin receptor (DTR) will render the CMs susceptible to diphtheria toxin (DT)-induced cell death

Fig. 2

Inflammation induced by cardiac injury. Sterile inflammation can be triggered by various components released by necrotic cells, including DAMPs, proteases, hydrolases and mitochondrial ROS. DAMPs directly activate PRRs on surveillant cells, including tissue macrophages, circulating monocytes and neutrophils, as well as on resident cells, including endothelial cells, fibroblasts and CMs. Proteases, hydrolases and ROS activate the complement system as well as inflammasomes, and degrade the ECM, altogether further propagating the inflammatory response. Activated tissue resident macrophages secrete cytokines to attract monocytes and neutrophils, activate endothelial cells to promote cell adhesion and permeability, and remodel the ECM. Infiltrating monocytes and neutrophils clear cell debris by phagocytosis and help terminate the initial insult. After wound clearance, myofibroblasts secrete ECM to help prevent the injured heart from rupturing. Differentiated Tregs tune down the inflammation by secreting anti-inflammatory cytokines, in parallel with M1–M2 macrophage polarization and programmed neutrophil apoptosis. Inflammation initiation, propagation and resolution can occur in both regenerative and non-regenerative models. However, in the regenerative models, these processes seem to facilitate CM dedifferentiation and proliferation and scar resolution by mechanisms yet to be determined

Fig. 3

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

Fig. 4

Comparative analyses in neonatal and adult mice after cardiac injury. In neonatal mice, embryonic macrophages with M2-like properties expand and dominate the injured area, leading to minimal inflammation, angiogenesis, and vigorous CM proliferation. T cells are also prone to differentiate into Tregs at this stage, resolving inflammation and stimulating CM proliferation by secreting mitogens [138]. The high reparative capacity leads to functional recovery in neonatal mice. However, in adult mice, this M2-like resident macrophage population is replaced, or out-numbered, by monocyte-derived macrophages which are prominently pro-inflammatory [59]. This functional difference leads to an unresolved scar and contractile dysfunction

Acknowledgments:
ZFIN wishes to thank the journal Cellular and molecular life sciences : CMLS for permission to reproduce figures from this article. Please note that this material may be protected by copyright. Full text @ Cell. Mol. Life Sci.