Li Changyong, Kong Yaxian, Wang Hong, Wang Shuling, Yu Hao, Liu Xin, Yang Lin, Jiang Xiangming, Li Lingsong, Li Liying
Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069, China.
J Hepatol. 2009 Jun;50(6):1174-83. doi: 10.1016/j.jhep.2009.01.028. Epub 2009 Mar 29.
BACKGROUND/AIMS: Myofibroblasts play a central role in the pathogenesis of liver fibrosis. Myofibroblasts of bone marrow (BM) origin have recently been identified in fibrotic liver. However, little is known about the mechanism that controls their mobilization in vivo. Here we confirmed that BM mesenchymal stem cells (BMSCs) can migrate to the damaged liver and differentiate into myofibroblasts. We also investigated the mechanism underlying the homing of BMSCs after liver injury.
ICR mice were lethally irradiated and received BM transplants from enhanced green fluorescent protein transgenic mice. Carbon tetrachloride or bile duct ligation was used to induce liver fibrosis. The fibrotic liver tissue was examined by immunofluorescent staining to identify BM-derived myofibroblasts.
BMSCs contributed significantly to myofibroblast population in fibrotic liver. Moreover, analysis in vivo and in vitro suggested that homing of BMSCs to the damaged liver was in response to sphingosine 1-phosphate (S1P) gradient between liver and BM. Furthermore, S1P receptor type 3 (S1P3) was required for migration of BMSCs triggered by S1P.
S1P mediates liver fibrogenesis through homing of BMSCs via S1P3 receptor, which may represent a novel therapeutic target in liver fibrosis through inhibiting S1P formation and/or receptor activation.
背景/目的：肌成纤维细胞在肝纤维化发病机制中起核心作用。最近在纤维化肝脏中发现了骨髓来源的肌成纤维细胞。然而，关于体内控制其动员的机制知之甚少。在此，我们证实骨髓间充质干细胞（BMSCs）可迁移至受损肝脏并分化为肌成纤维细胞。我们还研究了肝损伤后BMSCs归巢的潜在机制。
对ICR小鼠进行致死性照射，并接受来自增强型绿色荧光蛋白转基因小鼠的骨髓移植。采用四氯化碳或胆管结扎诱导肝纤维化。通过免疫荧光染色检查纤维化肝组织以鉴定骨髓来源的肌成纤维细胞。
BMSCs对纤维化肝脏中肌成纤维细胞群体有显著贡献。此外，体内和体外分析表明，BMSCs向受损肝脏的归巢是对肝脏与骨髓之间鞘氨醇-1-磷酸（S1P）梯度的反应。此外，S1P触发的BMSCs迁移需要3型S1P受体（S1P3）。
S1P通过经由S1P3受体的BMSCs归巢介导肝纤维化，这可能代表通过抑制S1P形成和/或受体激活来治疗肝纤维化的新靶点。
