Some species, such as salamanders and zebrafish, exhibit proficient regeneration, in that individuals are capable of regrowing lost tissue in organs and limbs and central nervous system without scarring. In adult mammals, the result of injury is scarring rather than regrowth, even though embryos are capable of both initial growth and later complete regeneration. Following the hypothesis that mechanisms of proficient regeneration do in fact exist in adult mammals, but are in some way silenced, the research community is engaged in trying to identify the specific differences between mammals and highly regenerative species that determine whether regrowth or scarring takes place following injury.
One of the more interesting discoveries of recent years is that differences in the behavior of the innate immune cells known as macrophages appear important. In the central nervous system, microglia are the analogous, very similar cell type. Macrophages and microglia involve themselves in the interactions between various types of somatic cells, stem cells, and progenitor cells that take place during regeneration.
In today’s research materials, researchers investigate some of the proteins that appear to change the behavior of microglia to allow for regeneration in the brains of zebrafish. Interestingly, one of them is TDP-43, which is implicated in neurodegeneration in humans due to its ability to misfold and form aggregates. The other, granulin, mediates clearance of TDP-43 aggregates. The work may prove to have relevance not just to inducing regeneration in the central nervous system, but also to addressing forms of neurodegeneration in which TDP-43 plays a prominent role.
In contrast to mammals, the central nervous system (CNS) of zebrafish has exceptional regenerative powers. In the case of injury, neural stem cells generate long-lived neurons, among other responses. Furthermore, CNS injuries prompt merely transitory reactivity of glial cells in zebrafish, which facilitates the integration of nerve cells into injured regions of the tissue.
The scientists deliberately inflicted CNS lesions in zebrafish, prompting the activation of microglia. At the same time, the researchers found an accumulation of lipid droplets and TDP-43 condensates in the lesions. To date, the protein TDP-43 has been primarily associated with neurodegenerative diseases. Granulin also played an important role in the zebrafish model. This protein contributed to the removal of the lipid droplets and TDP-43 condensates, whereupon the microglia transitioned from their activated to their resting form. The unscarred regeneration of the injury was the outcome. Zebrafish with experimentally induced granulin deficiency, by contrast, exhibited poor regeneration of the injury similar to what we see in mammals.
Decreasing the activation of pathology-activated microglia is crucial to prevent chronic inflammation and tissue scarring. In this study, we used a stab wound injury model in zebrafish and identified an injury-induced microglial state characterized by the accumulation of lipid droplets and TDP-43+ condensates. Granulin-mediated clearance of both lipid droplets and TDP-43+ condensates was necessary and sufficient to promote the return of microglia back to the basal state and achieve scarless regeneration.
Moreover, in postmortem cortical brain tissues from patients with traumatic brain injury, the extent of microglial activation correlated with the accumulation of lipid droplets and TDP-43+ condensates. Together, our results reveal a mechanism required for restoring microglia to a nonactivated state after injury, which has potential for new therapeutic applications in humans.