Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Am J Pathol. 2011 Jul;179(1):189-98. doi: 10.1016/j.ajpath.2011.03.049. Epub 2011 May 19.
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 α1(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-β1 (TGF-β1) and liposaccharide in vitro and in vivo, which suggests that release of TGF-β1 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.
CD45(+)和胶原 I 阳性（Col(+)）成纤维细胞参与皮肤、肺和肾脏的纤维化发生。使用分别由α1(I)胶原启动子和增强子控制的荧光素酶（Col-Luc→wt）或绿色荧光蛋白（Col-GFP→wt）表达的嵌合小鼠的骨髓（BM），研究了成纤维细胞对肝损伤的迁移反应。通过荧光素酶表达监测，在 CCl4 损伤的肝脏和脾脏中检测到成纤维细胞的募集。CCR2 和 CCR1 分别调节 CD45(+)Col(+)成纤维细胞的迁移，这分别表现为 Col-Luc(CCR2-/-)→wt 和 Col-Luc(CCR1-/-)→wt 小鼠中成纤维细胞迁移的 50%和 25%抑制。除了 CCR2 和 CCR1 之外，BM CD45(+)Col(+)细胞的迁出还受到转化生长因子-β1（TGF-β1）和脂多糖的调节，这表明 TGF-β1 的释放和肠道通透性的增加在成纤维细胞迁移中具有重要作用。在受损的肝脏中，成纤维细胞产生（肌）成纤维细胞。此外，在体外和体内鉴定出一种具有在培养中分化为成纤维细胞能力的 BM CD45(+)Col(+)细胞群体。在老年小鼠中，即使在没有损伤或应激的情况下，也可以检测到从 BM 中排出 CD45(+)Col(+)细胞，而在年轻小鼠中则没有。老年小鼠的肝纤维化也增加，并且与肝成纤维细胞数量增加相关。总之，成纤维细胞从 BM 迁移到肝脏，以响应肝损伤。它们的迁移受 CCR2 和 CCR1 调节，但随着年龄的增长而受损。
