Mice with a regenerative wound healing capacity and an SLE autoimmune phenotype contain elevated numbers of circulating and marrow-derived macrophage progenitor cells

Abstract

Mice from the MRL strain are prone to develop systemic lupus erythematosus (SLE) and have demonstrated accelerated wound healing and scarless tissue regeneration; however, many of the mechanisms involved in these clinically relevant pathologies are unclear. Prior studies have described macrophage accumulation and functional defects in mice prone to lupus. Monocyte-macrophages have also been shown to have a high degree of plasticity. To determine whether there might be innate differences in the hematopoietic systems of MRL mice, we evaluated hematopoietic progenitor cell content in a variety of tissues and the proliferative responses of derived marrow and thioglycolate (TG)-elicited peritoneal macrophages. Our experiments reveal that MRL mice have significantly lower numbers of circulating blood leukocytes and platelets. Even more strikingly, we found that MRL blood and marrow contain an unusually robust number of unique and assayable macrophage colony-stimulating factor responsive cells which have the characteristics of macrophage colony-forming cell precursors. In culture, in contrast to cells derived from control C57BL/6 mice, this cell type and thioglycolate-elicited peritoneal macrophages from MRL mice can be extensively expanded with just macrophage colony-stimulating factor to acquire an in situ "f-mac-like" (see Y. Zhao, D. Glesne and E. Huberman, A human peripheral blood monocyte-derived subset acts as pluripotent stem cells. Proc. Natl. Acad. Sci. U.S.A. 100, (2003) 2426-2431.) morphology when plated on plastic surfaces. Our results suggest that these increased numbers of macrophage progenitor cells and their potential differentiation plasticity may play a functional role in the onset of systemic lupus erythematosus and may also contribute to the accelerated and scarless tissue regenerative repair response observed in MRL mice.