Macrophages Needed for Zebrafish Regeneration

A fair number of research groups are investigating the low-level mechanisms of regeneration in animals such as salamanders and zebrafish, which are capable of regrowing limbs and even major internal organs. It is possible that the underlying biological machinery of this exceptional regeneration still exists in humans, but is merely dormant. Even if it has been lost over the course of evolutionary time it might be reintroduced if researchers just knew enough of the details. At this stage it is hard to say what the odds are, or how challenging it will be to achieve this goal - but that is what research is for. In recent years scientists have established that the immune cells known as macrophages are required for salamander regeneration to operate, and here a recent open access paper reports that this is the case for zebrafish as well:

Although wound healing has been extensively studied in mammals, we have a limited understanding of the injury-induced cellular response in a regenerative context. In this study, we utilized a combination of cell tracking and genetic cell ablation approaches to detail the course and role of cellular components of inflammation in zebrafish fin regeneration. Neutrophils and macrophages, as key mediators of inflammation, have defined functionally important roles in mammalian tissue repair. Our data suggest that the relative time frame of inflammatory cell movement to and from sites of injury is similar for adult zebrafish and mammals, where neutrophils are attracted to the wound first through 'homing' from the circulation, followed by circulation-based or resident macrophages.

We first tracked neutrophils and macrophages in adult zebrafish following amputation of the tail fin, and detailed a migratory timecourse that revealed conserved elements of the inflammatory cell response with mammals. Next, we used transgenic zebrafish in which we could selectively ablate macrophages, which allowed us to investigate whether macrophages were required for tail fin regeneration. We identified stage-dependent functional roles of macrophages in mediating fin tissue outgrowth and bony ray patterning, in part through modulating levels of blastema proliferation. Moreover, we also sought to detail molecular regulators of inflammation in adult zebrafish and identified Wnt/β-catenin as a signaling pathway that regulates the injury microenvironment, inflammatory cell migration and macrophage phenotype.

Our findings, coupled with recent research detailing pro-repair roles of inflammatory cells in zebrafish brain regeneration, advocate some degree of anatomical conservation of the role of injury components in regenerative process in zebrafish. Finally, macrophages may indeed form part of a cellular bridge between robustly regenerative organisms such as zebrafish and the less regenerative mammals that could potentially be manipulated for mammalian regenerative therapies.