Department of Gastroenterology, Justus-Liebig-University Giessen, Giessen, Germany.
Gut. 2012 Jun;61(6):907-16. doi: 10.1136/gutjnl-2011-300608. Epub 2011 Aug 25.
Reports on the effects of bone marrow-derived cells on hepatic fibrosis are contradictory. Impaired fibrosis but increased inflammation has recently been demonstrated 10 weeks after bone marrow transplantation (BM-Tx) in Abcb4-/- mice. It is hypothesised that BM-Tx might have long-term therapeutic potential by altering the immunological and matrix remodelling processes leading to hepatic regeneration.
After lethal irradiation of recipient mice, BM cells from GFP+ donor mice (allogeneic Tx) or Abcb4-/- mice (syngeneic Tx) were transplanted via tail vein injection. Readouts were performed 2, 10 and 20 weeks after Tx. Liver integrity was assessed serologically and histologically. Surrogate markers for fibrogenesis, T helper (Th) response, inflammation, graft-versus-host disease and fibrolysis were analysed by quantitative real-time PCR, zymography and immunohistology.
20 weeks after syngeneic and allogeneic BM-Tx, hepatic grading and staging were significantly improved. In contrast, 2 weeks after BM-Tx inflammatory grading, expression of inflammatory cell markers and associated chemokines and their receptors were increased and subsequently declined. In parallel, CD8+/GFP+ donor-derived T cells infiltrated the liver 2 weeks after BM-Tx. The Th1 cyokine interferon γ was increased 2 and 10 weeks after BM-Tx whereas the Th2 associated interleukin 13 was not altered. The gene expression of matrix metalloproteinases MMP-2, MMP-7, MMP-9 and MMP-13 was transiently upregulated and MMP-9 protein remained elevated 20 weeks after BM-Tx with enhanced gelatinase activity located within the fibrotic areas. Neutrophils were identified as major sources of MMP-9.
These results show that BM-Tx causes an antifibrotic Th1 response combined with transient inflammatory effects and subsequently upregulated MMP activity. Antifibrotic Th polarisation and prolonged proteolytic activity, especially of MMP-9, might be responsible for long-term amelioration of hepatic fibrosis.
骨髓来源细胞对肝纤维化的影响的报告结果相互矛盾。最近在 Abcb4-/- 小鼠骨髓移植（BM-Tx）后 10 周时，发现其纤维化受损但炎症增加。据推测，BM-Tx 通过改变导致肝再生的免疫和基质重塑过程，可能具有长期的治疗潜力。
在接受者小鼠致死性照射后，通过尾静脉注射来自 GFP+供体小鼠（同种异体 Tx）或 Abcb4-/- 小鼠（同基因 Tx）的 BM 细胞。在 Tx 后 2、10 和 20 周进行检测。通过血清学和组织学评估肝完整性。通过定量实时 PCR、酶谱分析和免疫组织化学分析，分析纤维化、辅助性 T 细胞（Th）反应、炎症、移植物抗宿主病和纤维蛋白溶解的替代标志物。
在同基因和同种异体 BM-Tx 后 20 周时，肝分级和分期显著改善。相比之下，在 BM-Tx 后 2 周时，炎症分级、炎症细胞标志物及其相关趋化因子和受体的表达增加，随后下降。同时，CD8+/GFP+供体衍生 T 细胞在 BM-Tx 后 2 周时浸润肝脏。BM-Tx 后 2 周和 10 周时，Th1 细胞因子干扰素 γ增加，而 Th2 相关细胞因子白细胞介素 13没有改变。基质金属蛋白酶 MMP-2、MMP-7、MMP-9 和 MMP-13 的基因表达短暂上调，并且在 BM-Tx 后 20 周时 MMP-9 蛋白仍然升高，并且在纤维化区域内的明胶酶活性增强。中性粒细胞被鉴定为 MMP-9 的主要来源。
这些结果表明，BM-Tx 导致抗纤维化 Th1 反应与短暂的炎症反应相结合，随后 MMP 活性上调。抗纤维化 Th 极化和持续的蛋白水解活性，特别是 MMP-9，可能是导致肝纤维化长期改善的原因。
