Homeostasis of peripheral macrophages are tuned by c-Kit+CD11b+ multipotent progenitor-like cells derived from mast cells.

KitW-sh/W-sh mice had been widely used to study mast cell (MC) functions as a MC-deficient animal model. However, dysfunctions in the other hematopoietic cells caused by the impaired Kit signaling were at times not suitable for analyzing MC functions in vivo. To overcome this pitfall, recently established Cpa3Cre/+ mice due to the genotoxicity of Cre recombinase in Cpa3 expressing MC were reportedly a better MC-deficient model. However, we unexpectedly found that CD206+ dermal macrophages and CD11bhi F4/80hi peritoneal macrophages in Cpa3Cre/+ mice (as well as KitW-sh/W-sh mice) were significantly decreased compared to those in wild type (WT) mice. Any decreased numbers of macrophages above described were recovered to the WT levels after reconstitutions of MCs by i.d. or i.p. injections of bone marrow-derived MCs (BMMCs) from WT mice (MC knock-in mice). We also found that c-Kit+CD11b+ cells in the peritoneal cavity were not detected in both MC-deficient strains and were significantly increased in MC knock-in mice by i.p. injecting BMMCs. These c-Kit+CD11b+ cells expressed Sca-1, CD34, and CD135, indicating the similar surface marker profiles to multipotent progenitor (MPP) phenotypes. We termed these cells “MPP-like cells”. In i.p. MC knock-in mice, MPP-like cells were derived from recipient cells in wild-type and Cpa3Cre/+ mice, whereas they were derived from donor MCs in KitW-sh/W-sh mice, indicating that Kit signaling is essential for generating MPP-like cells. Taken together, these results suggest that MCs play a role in controlling a population of MPP-like cells as a macrophage progenitor cells to regulate homeostasis of macrophages in terms of their numbers and phenotypes in a tissue-dependent manner.