Bone marrow-derived cells express matrix metalloproteinases and contribute to regression of liver fibrosis in mice
Bone marrow-derived cells express matrix metalloproteinases and contribute to regression of liver fibrosis in mice
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DOI：
10.1002/hep.21477
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发表时间：
2007-01-01
期刊：
影响因子：
13.5
通讯作者：
Okazaki, Isao
中科院分区：
文献类型：
--
作者：
Higashiyama, Reiichi;Inagaki, Yutaka;Okazaki, Isao
肝纤维化通常是进行性的，但如果病原体被充分清除或患者得到有效治疗，它偶尔是可逆的。然而，对这种肝纤维化可逆性的分子机制知之甚少。为了揭示骨髓（BM）来源的细胞对肝纤维化自发消退的贡献，在用增强的绿色荧光蛋白（EGFP）表达的BM细胞进行造血重建后，用重复四氯化碳注射处理小鼠。在四氯化碳中毒停止后的不同时间点，观察肝纤维化组织中EGFP阳性（EGFP（+））细胞的分布和特征。在肝纤维化高峰期肝组织中观察到大量EGFP（+）细胞，在肝纤维化恢复期间减少。其中一些，以及绿色荧光蛋白阴性（绿色荧光蛋白-）肝驻留细胞，表达基质金属蛋白酶（MMP）-13和NIMP-9。而MMP-13主要在门静脉周围区域的细胞簇中瞬时表达，MMP-9的表达和酶活性在位于汇管区和沿着纤维间隔的几种不同类型的细胞中检测到的分辨率过程。粒细胞集落刺激因子（G-CSF）治疗的BM细胞的治疗性募集显着增强BM衍生细胞迁移到纤维化的肝脏，并加速肝纤维化的消退。使用过表达肝细胞生长因子（HGF）的转基因小鼠的实验表明，G-CSF和HGF协同增加MMP-9表达沿着纤维间隔。结论：自体骨髓细胞有助于肝纤维化的自发消退，其治疗衍生可能是难治性肝纤维化的新治疗策略。
Liver fibrosis is usually progressive, but it can occasionally be reversible if the causative agents are adequately removed or if patients are treated effectively. However, molecular mechanisms responsible for this reversibility of liver fibrosis have been poorly understood. To reveal the contribution of bone marrow (BM)-derived cells to the spontaneous regression of liver fibrosis, Mice were treated with repeated carbon tetrachloride injections after hematopoietic reconstitution with enhanced green fluorescent protein (EGFP)-expressing BM cells. The distribution and characteristics of EGFP-positive (EGFP(+)) cells present in fibrotic liver tissue were examined at different time points after cessation of carbon tetrachloride intoxication. A large number of EGFP(+) cells were observed in liver tissue at peak fibrosis, which decreased during the recovery from liver fibrosis. Some of them, as well as EGFP-negative (EGFP-) liver resident cells, expressed matrix metalloproteinase (MMP)-13 and NIMP-9. Whereas MMP-13 was transiently expressed mainly in the cells clustering in the periportal areas, MMP-9 expression and enzymatic activity were detected over the resolution process in several different kinds of cells located in the portal areas and along the fibrous septa. Therapeutic recruitment of BM cells by granulocyte colony-stimulating factor (G-CSF) treatment significantly enhanced migration of BM-derived cells into fibrotic liver and accelerated the regression of liver fibrosis. Experiments using transgenic mice overexpressing hepatocyte growth factor (HGF) indicated that G-CSF and HGF synergistically increased MMP-9 expression along the fibrous septa. Conclusion: Autologous BM cells contribute to the spontaneous regression of liver fibrosis, and their therapeutic derivation could be a new treatment strategy for intractable liver fibrosis.