Migration of Fibrocytes in Fibrogenic Liver Injury

Abstract

CD45 ؉ and collagen I-positive (Col ؉ ) fibrocytes are implicated in fibrogenesis in skin, lungs, and kidneys. Fibrocyte migration in response to liver injury was investigated using bone marrow (BM) from chimeric mice expressing luciferase (Col-Luc¡wt) or green fluorescent protein (Col-GFP¡wt) under control of the ␣1(I) collagen promoter and enhancer, respectively. Monitored by luciferase expression, recruitment of fibrocytes was detected in CCl 4 -damaged liver and in spleen. Migration of CD45 ؉ Col ؉ fibrocytes was regulated by chemokine receptors CCR2 and CCR1, as demonstrated, respectively, by 50% and 25% inhibition of fibrocyte migration in Col-Luc CCR2؊/؊ ¡wt and Col-Luc CCR1؊/؊ ¡wt mice. In addition to CCR2 and CCR1, egress of BM CD45 ؉ Col ؉ cells was regulated by transforming growth factor-␤1 (TGF-␤1) and liposaccharide in vitro and in vivo, which suggests that release of TGF-␤1 and increased intestinal permeability have important roles in fibrocyte trafficking. In the injured liver, fibrocytes gave rise to (myo)fibroblasts. In addition, a BM population of CD45 ؉ Col ؉ cells capable of differentiation into fibrocytes in culture was identified. Egress of CD45 ؉ Col ؉ cells from BM was detected in the absence of injury or stress in aged mice but not in young mice. Development of liver fibrosis was also increased in aged mice and correlated with high numbers of liver fibrocytes. In conclusion, in response to liver injury, fibrocytes migrate from BM to the liver. Their migration is regulated by CCR2 and CCR1 but is compromised with age.

Cellular Mechanisms of Tissue Fibrosis. 3. Novel mechanisms of kidney fibrosis

“…These studies indicate that in animal models of kidney disease, cells of leukocyte origin are not a significant source of fibrillar matrix-forming cells or myofibroblasts (14, 64 -66). Importantly, similar findings have been reported using stringent experiments in liver, lung, skin, and muscle (82,86).…”

Inflammatory Chemokines MIP-1δ and MIP-3α Are Involved in the Migration of Multipotent Mesenchymal Stromal Cells Induced by Hepatoma Cells

“…Bone marrow fibrocyte migration into CCl4-damaged liver is regulated by CCR1 and CCR2 [55]. As MIP-1d is secreted by Huh-7 cells and induces MSC migration, we investigated its implication in the differentiation of MSC into myofibroblasts.…”

Origin of myofibroblasts in the fibrotic liver in mice

“…Hepatic myofibroblasts may originate from bone marrow (BM)-derived mesenchymal cells and fibrocytes, but only a small contribution of BM-derived cells to the myofibroblast population has been detected in experimental liver fibrosis (3)(4)(5). Another potential source of myofibroblast is epithelial-to-mesenchymal transition (EMT), in which epithelial cells acquire a mesenchymal phenotype and may give rise to fully differentiated myofibroblasts.…”