Macrophages are required to coordinate mouse digit tip regeneration

In mammals, macrophages are known to play a major role in tissue regeneration. These cells contribute to inflammation, histolysis, re-epithelialization, re-vascularization and cell proliferation. While macrophages have been shown to be essential for regeneration in salamanders and fish, their role has not been elucidated in mammalian epimorphic regeneration. Here, using the regenerating mouse digit tip as a mammalian model, we demonstrate that macrophages are essential for the regeneration process. Using cell depletion strategies, we show that regeneration is completely inhibited; bone histolysis does not occur, wound re-epithelization is inhibited and the blastema does not form. While rescue of epidermal wound closure, in the absence of macrophages, promotes blastema accumulation it does not rescue cell differentiation indicating that macrophages play a key role in the re-differentiation of the blastema. Further, we provide additional evidence that while bone degradation is a part of the regenerative process, it is not essential to the overall regenerative process. These findings show that macrophages play an essential role in coordinating the epimorphic regenerative response in mammals.