慢性肝损伤后形成的肌成纤维细胞和癌相关成纤维细胞主要来源于肝窦周星形细胞。

Perivenous Stellate Cells Are the Main Source of Myofibroblasts and Cancer-Associated Fibroblasts Formed After Chronic Liver Injuries.

机构信息

Department of Hepatic Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.

State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.

出版信息

Hepatology. 2021 Sep;74(3):1578-1594. doi: 10.1002/hep.31848.

DOI:10.1002/hep.31848

PMID:33817801

Abstract

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-β signaling links HSC activation to liver fibrosis and tumorigenesis.

摘要

背景与目的

由于缺乏能够在体内特异性和诱导性地对这些细胞进行命运映射的遗传工具，因此对纤维发生的 HSCs 的特性和病理生理学的研究受到了阻碍。在这里，我们通过对小鼠肝非实质细胞进行单细胞 RNA 测序，鉴定出转录因子 21（Tcf21）作为一种独特的标记物，其表达仅限于静止的 HSCs。

方法和结果

通过 Tcf21-CreER（受 Tcf21 基因启动子控制的 Cre-雌激素受体融合蛋白）追踪 Tcf21 细胞，靶向了约 10%的所有 HSCs，其中大多数位于门脉周围和中央区域。这些 HSCs 在稳态下处于静止状态，但在损伤时会被激活，在纤维化肝脏中产生 62%-67%的所有肌成纤维细胞和肝脏肿瘤中约 85%的所有癌相关成纤维细胞（CAFs）。通过 Tcf21-CreER 条件性缺失转化生长因子β受体 2（Tgfbr2）阻断了 HSC 的激活，损害了肝纤维化，并抑制了肝肿瘤的进展。