CD11b(+) Gr1(+) bone marrow cells ameliorate liver fibrosis by producing interleukin-10 in mice.
CD11b(+) Gr1(+) bone marrow cells ameliorate liver fibrosis by producing interleukin-10 in mice.
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DOI：
10.1002/hep.25817
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发表时间：
2012-11
期刊：
影响因子：
13.5
通讯作者：
Jeong, Won-Il
中科院分区：
文献类型：
--
作者：
Suh, Yang-Gun;Kim, Ja Kyung;Byun, Jin-Seok;Yi, Hyon-Seung;Lee, Young-Sun;Eun, Hyuk Soo;Kim, So Yeon;Han, Kwang-Hyub;Lee, Kwan Sik;Duester, Gregg;Friedman, Scott L.;Jeong, Won-Il
临床试验和动物模型表明，骨髓细胞（BMC）输注是治疗肝纤维化的有效方法，但其潜在机制尚不清楚，特别是与BMC早期效应相关的机制。在这里，我们分析了BMC输注的早期影响，并确定了BMC的亚群在四氯化碳诱导的肝纤维化小鼠中显示出抗纤维化作用。利用体外共培养系统研究了BMC与活化的肝星状细胞（HSC）之间的相互作用。在24小时内，输注的BMC与活化的HSC密切接触，这与减少肝纤维化，增强肝脏白细胞介素（IL）-10的表达，扩增调节性T细胞，但在BMC输注后24小时减少肝脏中的巨噬细胞浸润有关。相比之下，IL-10缺陷型（IL-10−/−）BMC未能在纤维化肝脏中重现这些作用。有趣的是，在分离的细胞中，CD 11b + Gr 1 highF 4/80−和CD 11b + Gr 1 +F4/80+ BMC在与活化的HSC共培养后表达更多的IL-10，导致HSC中胶原和α-平滑肌肌动蛋白的表达受到抑制。此外，当BMC与IL-6−/−和视黄醇脱氢酶1−/− HSC共培养时，这些作用分别增强或消除。与小鼠数据相似，人BMC与人HSC系（LX-2或hTERT）共培养后表达更多的IL-10，肝硬化患者自体BMC输注后血清IL-10水平显著升高。活化的HSC可增加BMC（CD 11b + Gr 1highF 4/80−和CD 11b + Gr 1 +F4/80+细胞）中IL-10的表达，从而改善肝纤维化。我们的研究结果可以加强BMC治疗肝纤维化的设计。
Clinical trials and animal models suggest that infusion of bone marrow cells (BMC) is effective therapy for liver fibrosis, but the underlying mechanisms are obscure, especially those associated with early effects of BMC. Here, we analyzed the early impact of BMC infusion and identified the subsets of BMC showing antifibrotic effects in mice with carbon tetrachloride-induced liver fibrosis. An interaction between BMC and activated hepatic stellate cells (HSCs) was investigated using in vitro co-culturing system. Within 24 hours, infused BMC were in close contact with activated HSCs, which was associated with reduced liver fibrosis, enhanced hepatic expression of interleukin (IL)-10, expanded regulatory T cells but decreased macrophage infiltration in the liver at 24 hours after BMC infusion. In contrast, IL-10-deficient (IL-10−/−) BMC failed to reproduce these effects in the fibrotic livers. Intriguingly, in isolated cells, CD11b+Gr1highF4/80− and CD11b+Gr1+F4/80+ BMC expressed more IL-10 after co-culturing with activated HSCs, leading to suppressed expression of collagen and α-smooth muscle actin in HSCs. Moreover, these effects were either enhanced or abrogated, respectively, when BMC were co-cultured with IL-6−/− and retinaldehyde dehydrogenase 1−/− HSCs. Similar to murine data, human BMC expressed more IL-10 after co-culturing with human HSC lines (LX-2 or hTERT), and serum IL-10 levels were significantly elevated in patients with liver cirrhosis after autologous BMC infusion. Activated HSCs increase IL-10 expression in BMC (CD11b+Gr1highF4/80− and CD11b+Gr1+F4/80+ cells), which in turn ameliorates liver fibrosis. Our findings could enhance the design of BMC therapy for liver fibrosis.
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