Role of Macrophages in Epimorphic Tissue Regeneration.

BACKGROUND: Macrophages are phagocytic cells involved in a wide range of biological processes, including epimorphic regeneration. Studies using several models of epimorphosis have revealed that macrophages contribute to the proliferation and survival of dedifferentiated cells required for blastema formation. They also regulate inflammatory response, control fibrosis, and participate in the differentiation of the newly formed tissues. It is noteworthy that macrophages are highly responsive to external signals, generating several phenotypic subpopulations supporting the progression of the regeneration process. Additionally, evidence suggests that tissue-resident macrophages contribute to epimorphosis, whereas circulating monocyte-derived macrophages can acquire either regenerative or inflammatory phenotypes depending on environmental signals present in the injured structure. SUMMARY: Given that recent reviews of macrophage involvement in epimorphic regeneration have focused predominantly on zebrafish, this review aims to summarize evidence from other regenerative vertebrate models in which these cells play essential roles, including salamander limb and lens regeneration, lizard tail regeneration, and rodent fingertip and ear regeneration. Additionally, we highlight the most notable mechanisms by which macrophages promote regeneration in each model and discuss the influence of the microenvironment on macrophage phenotype acquisition, as well as current understanding of the role of tissue-resident macrophages in this process. KEY MESSAGES: Macrophages are key promoters of epimorphic regeneration. Evidence indicates that tissue-resident macrophages are the primary macrophage population involved in regulating several processes essential for regeneration, including re-epithelialization, blastema formation, extracellular matrix remodeling and, the regulation of inflammation through the secretion of soluble factors. Given that a large proportion of tissue-resident macrophages are establishing during embryo development, it is possible that they retain a development program that influences the regenerative microenvironment.