CXCL16 Recruits Bone Marrow-Derived Fibroblast Precursors in Renal Fibrosis

Abstract

Although fibroblasts are responsible for the production and deposition of extracellular matrix in renal fibrosis, their origin is controversial. Circulating fibroblast precursors may contribute to the pathogenesis of renal fibrosis, but the signaling mechanisms underlying the recruitment of bone marrow-derived fibroblast precursors into the kidney in response to injury are incompletely understood. Here, in the unilateral ureteral obstruction model of renal fibrosis, tubular epithelial cells upregulated the chemokine CXCL16 in obstructed kidneys, and circulating fibroblast precursors expressed the CXCL16 receptor, CXCR6. Compared with wild-type mice, CXCL16-knockout mice accumulated significantly fewer bone marrow-derived fibroblast precursors in obstructed kidneys. CXCL16-knockout mice also exhibited significantly fewer CD45-, collagen I-, and CXCR6-triple-positive fibroblast precursors in injured kidneys. Furthermore, targeted deletion of CXCL16 inhibited myofibroblast activation, reduced collagen deposition, and suppressed expression of collagen I and fibronectin. In conclusion, CXCL16 contributes to the pathogenesis of renal fibrosis by recruiting bone marrow-derived fibroblast precursors.

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Other embryonic sources were also proposed, for example from protein zero (P0) neural crest progenitors (166). A considerable number of studies have tackled the source of myofibroblasts during renal fibrosis (22,62,67,83,(172)(173)(174)(175)(176)(177)(178). In short, and in our opinion, the majority, if not all myofibroblasts arise from resident interstitial mesenchymal cells.…”

The Role of Bone Marrow-Derived Fibroblasts in Renal Fibrosis

“…We have recently provided unequivocal evidence that bone marrow-derived fibroblasts accumulate in the kidney in response to obstructive injury [9]. We demonstrate that CD45 and vimentin dual positive fibroblasts or CD11b and vimentin dual positive fibroblasts accumulate in the kidney in response to obstructive injury using confocal microscope.…”

“…Recent evidence indicates that they may originate from bone marrow-derived progenitor cells [5][6][7][8][9]. A study of mismatched kidney transplantation in humans has shown that the proportion of host-derived SMA-positive cells is approximately 30% in allografts undergoing chronic rejection compared with 10% in those without rejection [7].…”

“…A study of mismatched kidney transplantation in humans has shown that the proportion of host-derived SMA-positive cells is approximately 30% in allografts undergoing chronic rejection compared with 10% in those without rejection [7]. In rodent models of renal fibrosis, several studies using bone marrow transplantation have shown that bone marrow-derived fibroblasts migrate into the kidney in response to injury [5,[8][9][10][11][12]. For example, one study using bone marrow transplantation of transgenic mice that express enhanced green fluorescence protein (GFP) under the control of the fibroblast specific protein 1 (FSP1) promoter has demonstrated that 15% of bone marrow-derived fibroblasts are present in the kidney 10 days after obstructive injury [5].…”

TNF/Ang-II synergy is obligate for fibroinflammatory pathology, but not for changes in cardiorenal function

“…This finding was unexpected, as we have previously observed a critical role for CXCL16 in UUO and Ang‐II/uninephrectomy‐induced renal injury (Chen et al. 2011; Xia et al. 2013).…”