Perivenous Stellate Cells Are the Main Source of Myofibroblasts and Cancer-Associated Fibroblasts Formed After Chronic Liver Injuries
Perivenous Stellate Cells Are the Main Source of Myofibroblasts and Cancer-Associated Fibroblasts Formed After Chronic Liver Injuries
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静脉周围星状细胞是慢性肝损伤后形成的肌成纤维细胞和癌症相关成纤维细胞的主要来源
DOI：
10.1002/hep.31848
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发表时间：
2021-09-01
期刊：
影响因子：
13.5
通讯作者：
Zhou, Bo O.
中科院分区：
文献类型：
--
作者：
Wang, Shan-Shan;Tang, Xinyu Thomas;Zhou, Bo O.
背景与目的 由于缺乏能在体内对致纤维化肝星状细胞（HSCs）进行特异性和诱导性命运示踪的遗传工具，对这些细胞的特性及病理生理学研究受到了阻碍。在此，通过对小鼠肝脏非实质细胞进行单细胞RNA测序，我们鉴定出转录因子21（Tcf21）是一种独特的标志物，其表达仅限于静止期的HSCs。
方法与结果 通过Tcf21 - CreER（由Tcf21基因启动子控制的Cre - 雌激素受体融合蛋白）对Tcf21⁺细胞进行示踪，发现其靶向约10%的所有HSCs，其中大多数位于门静脉周围和中央静脉周围区域。这些HSCs在稳态下处于静止状态，但在受到损伤时会被激活，在纤维化肝脏中产生62% - 67%的肌成纤维细胞，在肝脏肿瘤中产生约85%的癌相关成纤维细胞（CAFs）。利用Tcf21 - CreER条件性敲除转化生长因子β受体2（Tgfbr2）可阻断HSC激活、减轻肝纤维化并抑制肝脏肿瘤进展。
结论 总之，Tcf21 - CreER靶向的静脉周围星状细胞是慢性损伤肝脏中肌成纤维细胞和CAFs的主要来源。TGF - β信号通路将HSC激活与肝纤维化及肿瘤发生联系起来。
Background and Aims Studies of the identity and pathophysiology of fibrogenic HSCs have been hampered by a lack of genetic tools that permit specific and inducible fate-mapping of these cells in vivo. Here, by single-cell RNA sequencing of nonparenchymal cells from mouse liver, we identified transcription factor 21 (Tcf21) as a unique marker that restricted its expression to quiescent HSCs. Approach and Results Tracing Tcf21(+) cells by Tcf21-CreER (Cre-Estrogen Receptor fusion protein under the control of Tcf21 gene promoter) targeted ~10% of all HSCs, most of which were located at periportal and pericentral zones. These HSCs were quiescent under steady state but became activated on injuries, generating 62%-67% of all myofibroblasts in fibrotic livers and ~85% of all cancer-associated fibroblasts (CAFs) in liver tumors. Conditional deletion of Transforming Growth Factor Beta Receptor 2 (Tgfbr2) by Tcf21-CreER blocked HSC activation, compromised liver fibrosis, and inhibited liver tumor progression. Conclusions In conclusion, Tcf21-CreER-targeted perivenous stellate cells are the main source of myofibroblasts and CAFs in chronically injured livers. TGF-beta signaling links HSC activation to liver fibrosis and tumorigenesis.