Hepatocyte growth factor mediates a novel form of hepatic stem/progenitor cell-induced tolerance in a rat xenogeneic liver rejection model
Hepatocyte growth factor mediates a novel form of hepatic stem/progenitor cell-induced tolerance in a rat xenogeneic liver rejection model
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DOI：
10.1016/j.intimp.2020.107180
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发表时间：
2021-01-12
影响因子：
5.6
通讯作者：
Bai, Lianhua
中科院分区：
文献类型：
--
作者：
Chen, Quanyu;You, Yu;Bai, Lianhua
我们之前已经鉴定出表达神经/胶质抗原 2 的新型肝干/祖细胞 (NG2+ HSP)，它们通过抑制免疫细胞反应而有益于组织修复。在这项体内研究中，我们研究了在成熟的叙利亚金仓鼠（SGH）至刘易斯（LEW）异种大鼠急性肝排斥（ARJ）模型中使用分泌肝细胞生长因子（HGF）的NG2（+）热休克蛋白作为耐受原。收集肝脏和血细胞，使用免疫荧光染色、蛋白质印迹、ELISA 和 TUNEL 测定进行组织学和功能分析。将所有受体大鼠随机分为5组（n = 14只大鼠/组），并进行处理：（1）ARJ + PBS：（2）ARJ + NG2：尾静脉注射NG2（+）HSP； (3) ARJ+他克莫司(FK506，口服)； (4) 在注射NG2(+) HSPs前24小时ARJ+抗cMet功能阻断抗体(a-cMet-Ab，I.V)； (5)ARJ+cHGF(临床常用HGF)。 LEW 至 LEW 同基因大鼠被认为是“正常”（n = 14，即 Syn）。 NG2(+) HSP 移植后观察到平均生存时间 (MST) 显着延长，移植物功能得到改善。抗cMet抗体显着阻断NG2(+) HSP的作用，表明该作用可能与NG2(+) HSP分泌的HGF有关。值得注意的是，当静脉注射到异种大鼠模型中时，注射的cHGF不仅延长了受体大鼠的MST，而且还增加了表达TUNEL的异种反应性细胞毒性T淋巴细胞（CD8+T细胞）的数量。基于这些结果，分泌HGF的NG2(+) HSPs可能通过诱导其凋亡来特异性靶向受体CD8(+) T细胞。 y
We have previously identified novel neural/glial antigen 2-expressing hepatic stem/progenitor cells (NG2+ HSPs) that are beneficial for tissue repair by inhibiting the immune cell response. In this in vivo study, we investigated the use of hepatocyte growth factor (HGF)-secreting NG2(+) HSPs as a tolerogen in the well established Syrian golden hamster (SGH) to Lewis (LEW) xenogeneic rat acute liver rejection (ARJ) model. Liver and blood cells were collected for histology and functional analyses using immunofluorescence staining, western blot, ELISA, and TUNEL assays. All recipient rats were randomly divided into 5 groups (n = 14 rats/group) and treated with: (1) ARJ + PBS: (2) ARJ + NG2: tail vein injection of NG2(+) HSPs; (3) ARJ + tacrolimus (FK506, oral administration); (4) ARJ + an anti-cMet functional blocking antibody (a-cMet-Ab, I.V) 24 h before the injection of NG2(+) HSPs; (5) ARJ + cHGF (clinically used HGF). LEW to LEW syngeneic rats were considered "normal" (n = 14, namely Syn). Significantly prolonged mean survival times (MSTs) and improved graft functions were observed after NG2(+) HSP transplantation. An anti-cMet Ab significantly blocked the effect of NG2(+) HSPs, suggesting that the effects were likely associated with HGF secreted from NG2(+) HSPs. Notably, when intravenously injected into the xenogeneic rat model, the injected cHGF not only prolonged the MST of recipient rats but also increased the number of TUNEL-expressing xenoreactive cytotoxic T lymphocytes (CD8(+) T cells). Based on these results, HGF-secreting NG2(+) HSPs may specifically target recipient CD8(+) T cells by inducing their apoptosis. y