Hepatocyte growth factor/c-met signaling is required for stem-cell-mediated liver regeneration in mice.
Hepatocyte growth factor/c-met signaling is required for stem-cell-mediated liver regeneration in mice.
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DOI：
10.1002/hep.24796
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发表时间：
2012-04
期刊：
影响因子：
13.5
通讯作者：
Thorgeirsson, Snorri S.
中科院分区：
文献类型：
--
作者：
Ishikawa, Tsuyoshi;Factor, Valentina M.;Marquardt, Jens U.;Raggi, Chiara;Seo, Daekwan;Kitade, Mitsuteru;Conner, Elizabeth A.;Thorgeirsson, Snorri S.
HGF/c-Met 支持控制干细胞稳态的多效信号转导途径。在这里，我们通过利用携带 c-met floxed 等位基因和 Alb-Cre 或 Mx1-Cre 转基因的小鼠，直接探讨了 c-Met 在干细胞介导的肝再生中的作用。为了激活卵圆细胞，即肝干细胞 (HSC) 后代，我们使用了由含有卟啉原剂 3, 5-二乙羰基-1,4-二氢可力丁 (DDC) 的饮食诱导的肝损伤模型。通过对 FACS 分选的 EpCam 阳性细胞进行 PCR 分析，证实了两种模型中卵圆细胞中 c-met 的缺失。使用卵圆抗体（A6 和 EpCam）和肝细胞特异性（HNF-4α）抗体进行双重免疫荧光显示，c-Met 受体的缺失会降低卵圆细胞体外成球能力，并减少卵圆细胞池、体内迁移受损和肝细胞分化减少。此外，c-Met 的缺乏对 HSC 生态位的组织重塑和整体组成产生深远影响，这与 MMP9 活性大大降低和 SDF1 表达减少有关。对分离的细胞群使用细胞类型特异性标记物的双重免疫荧光与 MMP9 和明胶酶谱分析相结合，我们确定巨噬细胞是 DDC 处理的肝脏中 MMP9 的主要来源。与 c-Metfl/fl 中实现的上皮细胞谱系选择性失活相比，Mx1-Cre 驱动的 c-met 缺失对 HSC 反应产生最大的表型影响； Alb-Cre+/- 小鼠。然而，在这两种模型中，c-met 的遗传缺失引发了类似的级联事件，导致 HSC 动员失败和小鼠死亡。结论：这些结果证实了 c-Met 在调节 HSC 反应中的直接贡献，并支持 HGF/c-Met 作为患病肝脏再生的重要生长因子信号通路的独特作用。
HGF/c-Met supports a pleiotrophic signal transduction pathway that controls stem cell homeostasis. Here, we directly addressed the role of c-Met in stem cell-mediated liver regeneration by utilizing mice harboring c-met floxed alleles and Alb-Cre or Mx1-Cre transgenes. To activate oval cells, the hepatic stem cell (HSC) progeny, we used a model of liver injury induced by diet containing the porphyrinogenic agent, 3, 5-diethocarbonyl-1,4-dihydrocollidine (DDC). Deletion of c-met in oval cells was confirmed in both models by PCR analysis of FACS- sorted EpCam-positive cells. Loss of c-Met receptor decreased sphere-forming capacity of oval cells in vitro as well as reduced oval cell pool, impaired migration and decreased hepatocytic differentiation in vivo as demonstrated by double immunofluorescence using oval- (A6 and EpCam) and hepatocyte-specific (HNF-4α) antibodies. Furthermore, lack of c-Met had a profound effect on tissue remodeling and overall composition of HSC niche which was associated with greatly reduced MMP9 activity and decreased expression of SDF1. Using a combination of double immunofluorescence of cell type-specific markers with MMP9 and gelatin zymography on the isolated cell populations, we identified macrophages as a major source of MMP9 in DDC-treated livers. The Mx1-Cre-driven c-met deletion caused the greatest phenotypic impact on HSCs response as compared to the selective inactivation in the epithelial cell lineages achieved in c-Metfl/fl; Alb-Cre+/- mice. However, in both models, genetic loss of c-met triggered a similar cascade of events leading to failure of HSCs mobilization and death of the mice. Conclusion: These results establish a direct contribution of c-Met in regulation of HSC response, and support a unique role for HGF/c-Met as an essential growth factor signaling pathway for regeneration of diseased liver.
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影响因子：
3.7
作者：
Factor, Valentina M.;Seo, Daekwan;Thorgeirsson, Snorri S.
通讯作者：
Thorgeirsson, Snorri S.
影响因子：
4.2
作者：
Bellayr IH;Mu X;Li Y
通讯作者：
Li Y
DOI：
10.2183/pjab.86.588
发表时间：
2010
期刊：
Proceedings of the Japan Academy. Series B, Physical and biological sciences
影响因子：
--
作者：
Nakamura T;Mizuno S
通讯作者：
Mizuno S
影响因子：
13.5
作者：
Higashiyama, Reiichi;Inagaki, Yutaka;Okazaki, Isao
通讯作者：
Okazaki, Isao
影响因子：
15.9
作者：
Kollet, O;Shivtiel, S;Lapidot, T
通讯作者：
Lapidot, T