Healing power: The mammalian macrophage in skeletal regeneration, scar formation, and regenerative medicine

Common to all types of injuries, inflammation is the initial stage of healing. The final outcome of healing, however, can be quite distinct after different types of injuries. Some tissues, such as bone, excel at regenerating damaged structures while other tissues, for example skin, heal via deposition of excessive, unpatterned collagen. How does the initial inflammatory environment pave the way for regeneration or fibrosis in mammals? In this review, we look at three wound healing paradigms in mammals: fibrosis (i.e. scar formation of skin), tissue-specific regeneration, (i.e. fracture healing), and epimorphic regeneration (i.e. blastema-mediated skeletal regeneration). We discuss the roles that innate immune cells, specifically macrophages, play in each type of repair response in an attempt to synthesize where similarities and differences have been observed across wound healing models. By juxtaposing the roles of macrophages in regeneration and fibrotic healing in this way, we aim to gain insight into how the initial tissue environment sets the stage for the healing outcome. Finally, we discuss how regenerative medicine could capitalize on aspects of the immune response to promote regeneration over fibrotic healing.