Portal fibroblasts marked by the surface antigen Thy1 contribute to fibrosis in mouse models of cholestatic liver injury.
Portal fibroblasts marked by the surface antigen Thy1 contribute to fibrosis in mouse models of cholestatic liver injury.
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DOI：
10.1002/hep4.1023
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发表时间：
2017-05
影响因子：
5.1
通讯作者：
Itoh T
中科院分区：
文献类型：
--
作者：
Katsumata LW;Miyajima A;Itoh T
肝纤维化是一种以包括胶原在内的细胞外基质的过度产生和积累为特征的疾病，是不同病因的慢性肝损伤最常见的结果。储存维生素A的肝星状细胞（hsc）被认为是这种胶原蛋白产生的主要来源，在肝损伤时被激活。相比之下，由于缺乏特异性表面标记物来鉴定和分离这些细胞以进行详细分析，其他细胞类型对这种纤维化反应的贡献在很大程度上仍然难以捉摸。在这里，我们在小鼠肝脏中鉴定了胸腺细胞抗原1 (Thy1)+ CD45−细胞（Thy1 MCs）的间充质群体；这些细胞在体内存在于门静脉附近，并在体外通过胶原蛋白和α‐平滑肌肌动蛋白的表达显示出促纤维化特征。小鼠肝非实质细胞的流式细胞分析显示，维生素A的储存和Thy1的表达是相互排斥的，表明Thy1 MCs不同于hsc。重要的是，在胆汁淤积性肝损伤小鼠模型中，Thy1 MCs反应并促进肝纤维化的发展。随着胆汁淤积性肝损伤的发生，产生胶原的Thy1 MCs细胞数量增加，并通过上调基质金属蛋白酶抑制剂Timp1的表达抑制胶原降解，从而促进门静脉周围区细胞外基质的积累。结论：本研究建立了Thy1作为一种有用的细胞表面标记物，可以前瞻性地鉴定和分离门脉周围成纤维细胞，并进一步强调了这些细胞在胆汁淤积性肝损伤引起的肝纤维化发病机制中的重要作用。我们认为Thy1 MCs可能是治疗肝纤维化的一个有趣的治疗靶点，除了具有良好特征的hsc。（肝病通讯2017；1:198‐214）
Liver fibrosis, a condition that is characterized by excessive production and accumulation of extracellular matrix, including collagen, is the most common outcome of chronic liver injuries of different etiologies. Vitamin A‐storing hepatic stellate cells (HSCs) are considered to be the main source of this collagen production, with activation in response to liver injury. In contrast, the contribution of other cell types to this fibrogenic response remains largely elusive due to the lack of specific surface markers to identify and isolate these cells for detailed analysis. Here, we identify a mesenchymal population of thymus cell antigen 1 (Thy1)+ CD45− cells (Thy1 MCs) in the mouse liver; these cells reside near the portal vein in vivo and indicate profibrogenic characteristics in vitro, shown by their expression of collagen and α‐smooth muscle actin. Flow cytometric analysis of mouse liver nonparenchymal cells revealed that vitamin A storage and Thy1 expression were mutually exclusive, indicating that Thy1 MCs are distinct from HSCs. Importantly, Thy1 MCs reacted and contributed to the development of liver fibrosis specifically in mouse models of cholestatic liver injury. With the occurrence of cholestatic liver injury, collagen‐producing Thy1 MCs expanded in cell number and inhibited collagen degradation through up‐regulation of matrix metalloproteinase inhibitor Timp1 expression, thereby promoting the accumulation of extracellular matrix in the periportal area. Conclusion: This study establishes Thy1 as a useful cell surface marker to prospectively identify and isolate periportal fibroblasts and further highlights a significant contribution of these cells to the pathogenesis of liver fibrosis caused by cholestatic liver injuries. We suggest that Thy1 MCs may be an interesting therapeutic target for treating liver fibrosis in addition to the well‐characterized HSCs. (Hepatology Communications 2017;1:198‐214)
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影响因子：
13.5
作者：
Dranoff, Jonathan A.;Wells, Rebecca G.
通讯作者：
Wells, Rebecca G.
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
6
作者：
Liu, Daqing;Yovchev, Mladen I.;Dabeva, Mariana D.
通讯作者：
Dabeva, Mariana D.
DOI：
10.1073/pnas.82.24.8681
发表时间：
1985-12-01
影响因子：
11.1
作者：
FRIEDMAN, SL;ROLL, FJ;BISSELL, DM
通讯作者：
BISSELL, DM
影响因子：
2.3
作者：
Dudas, Jozsef;Mansuroglu, Tumen;Ramadori, Giuliano
通讯作者：
Ramadori, Giuliano