BACKGROUND: Chronic kidney disease (CKD) has been reported to be a serious risk factor for cardiovascular diseases such as cardio-renal syndrome (CRS). Dysregulation of tissue repair is a pathological process leading to the end stage of organ failure characterized by tissue fibrosis. However, fibrosis mediators in CRS under CKD are not fully understood.
METHODS: To search for cells responsible for the development of CRS, angiotensin II (AII) infusion plus unilateral ureteral obstruction (UUO) (AII+UUO) CRS model was established using CAG-GFP mice and Col1a2 (Col)-GFP mice along with procedures of parabiosis and bone-marrow transplantation (BMT). We performed flow cytometry to identify newly recruited cells into hearts or kidneys and gene expression analyses followed by cell sorting. We also used immunohistochemistry and co-culture system of sorted cells with mouse embryonic fibroblasts (MEFs) from Col-Luciferase mice.
RESULTS: We newly identified a cluster of myeloid cells, which was found to be double-positive for CD45 and Sca1 in hearts as well as kidneys of the CRS model. The cells of the cluster were oval-shaped and mononuclear and significantly increased in number in proportion to heart or kidney fibrosis. The CD45+Sca1+ cells had an activating potential for collagen production of cultured MEFs and also produced type 1 collagen by themselves. GeneChip analyses and flow cytometry revealed the subpopulation of CD45+Sca1+ cells, which expressed CCR8.
CONCLUSION: We identified a new population of myeloid-derived fibrosis-inducing cells, which could provide a new avenue in fibrosis.