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Theranostics 2024; 14(6):2379-2395. doi:10.7150/thno.91572 This issue Cite

Research Paper

Hepatic progenitor cell-originated ductular reaction facilitates liver fibrosis through activation of hedgehog signaling

Yonghong Hu1,2,4#, Xinyu Bao7,8#, Zheng Zhang1,2, Long Chen3, Yue Liang1,2, Yan Qu5, Qun Zhou3, Xiaoxi Zhou1,2, Jing Fang1,2, Zhun Xiao3, Yadong Fu3, Hailin Yang3, Wei Liu1,2, Ying Lv1,2, Hongyan Cao6, Gaofeng Chen1,2, Jian Ping1,2, Hua Zhang1,2, Yongping Mu1,2, Chenghai Liu1,2, Chao-Po Lin7,8✉, Jian Wu9,10,11✉, Ping Liu1,2,3✉, Jiamei Chen1,2✉

1. Institute of Liver diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
2. Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai 201203, China.
3. Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
4. Institute of Surgery of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
5. Department of Hepatobiliary Surgery, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
6. Department of Gastroenterology, Shanghai University of Traditional Chinese Medicine Shanghai TCM - Integrated hospital, Shanghai 201203, China.
7. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
8. Shanghai Clinical Research and Trial Center, Shanghai 201210, China.
9. Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China.
10. Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China.
11. Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai 200032, China.
#Equal contribution.

✉ Corresponding authors: Jiamei Chen, MD, PhD, Institute of Liver diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, S More

Citation:
Hu Y, Bao X, Zhang Z, Chen L, Liang Y, Qu Y, Zhou Q, Zhou X, Fang J, Xiao Z, Fu Y, Yang H, Liu W, Lv Y, Cao H, Chen G, Ping J, Zhang H, Mu Y, Liu C, Lin CP, Wu J, Liu P, Chen J. Hepatic progenitor cell-originated ductular reaction facilitates liver fibrosis through activation of hedgehog signaling. Theranostics 2024; 14(6):2379-2395. doi:10.7150/thno.91572. https://www.thno.org/v14p2379.htm
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Abstract

Graphic abstract

Background: It is poorly understood what cellular types participate in ductular reaction (DR) and whether DR facilitates recovery from injury or accelerates hepatic fibrosis. The aim of this study is to gain insights into the role of hepatic progenitor cell (HPC)-originated DR during fibrotic progression.

Methods: DR in liver specimens of PBC, chronic HBV infection (CHB) or NAFLD, and four rodent fibrotic models by different pathogenic processes was evaluated. Gli1 expression was inhibited in rodent models or cell culture and organoid models by AAV-shGli1 or treating with GANT61.

Results: Severity of liver fibrosis was positively correlated with DR extent in patients with PBC, CHB or NAFLD. HPCs were activated, expanded, differentiated into reactive cholangiocytes and constituted “HPC-originated DR”, accompanying with exacerbated fibrosis in rodent models of HPC activation & proliferation (CCl4/2-AAF-treated), Μdr2-/- spontaneous PSC, BDL-cholestatic fibrosis or WD-fed/CCl4-treated NASH-fibrosis. Gli1 expression was significantly increased in enriched pathways in vivo and in vitro. Enhanced Gli1 expression was identified in KRT19+-reactive cholangiocytes. Suppressing Gli1 expression by administration of AAV-shGli1 or GANT61 ameliorated HPC-originated DR and fibrotic extent. KRT19 expression was reduced after GANT61 treatment in sodium butyrate-stimulated WB-F344 cells or organoids or in cells transduced with Gli1 knockdown lentiviral vectors. In contrast, KRT19 expression was elevated after transducing Gli1 overexpression lentiviral vectors in these cells.

Conclusions: During various modes of chronic injury, Gli1 acted as an important mediator of HPC activation, expansion, differentiation into reactive cholangiocytes that formed DR, and subsequently provoked hepatic fibrogenesis.

Keywords: liver fibrosis, Gli1, ductular reaction, hepatic progenitor cells, reactive cholangiocytes

Citation styles

APA
Hu, Y., Bao, X., Zhang, Z., Chen, L., Liang, Y., Qu, Y., Zhou, Q., Zhou, X., Fang, J., Xiao, Z., Fu, Y., Yang, H., Liu, W., Lv, Y., Cao, H., Chen, G., Ping, J., Zhang, H., Mu, Y., Liu, C., Lin, C.P., Wu, J., Liu, P., Chen, J. (2024). Hepatic progenitor cell-originated ductular reaction facilitates liver fibrosis through activation of hedgehog signaling. Theranostics, 14(6), 2379-2395. https://doi.org/10.7150/thno.91572.

ACS
Hu, Y.; Bao, X.; Zhang, Z.; Chen, L.; Liang, Y.; Qu, Y.; Zhou, Q.; Zhou, X.; Fang, J.; Xiao, Z.; Fu, Y.; Yang, H.; Liu, W.; Lv, Y.; Cao, H.; Chen, G.; Ping, J.; Zhang, H.; Mu, Y.; Liu, C.; Lin, C.P.; Wu, J.; Liu, P.; Chen, J. Hepatic progenitor cell-originated ductular reaction facilitates liver fibrosis through activation of hedgehog signaling. Theranostics 2024, 14 (6), 2379-2395. DOI: 10.7150/thno.91572.

NLM
Hu Y, Bao X, Zhang Z, Chen L, Liang Y, Qu Y, Zhou Q, Zhou X, Fang J, Xiao Z, Fu Y, Yang H, Liu W, Lv Y, Cao H, Chen G, Ping J, Zhang H, Mu Y, Liu C, Lin CP, Wu J, Liu P, Chen J. Hepatic progenitor cell-originated ductular reaction facilitates liver fibrosis through activation of hedgehog signaling. Theranostics 2024; 14(6):2379-2395. doi:10.7150/thno.91572. https://www.thno.org/v14p2379.htm

CSE
Hu Y, Bao X, Zhang Z, Chen L, Liang Y, Qu Y, Zhou Q, Zhou X, Fang J, Xiao Z, Fu Y, Yang H, Liu W, Lv Y, Cao H, Chen G, Ping J, Zhang H, Mu Y, Liu C, Lin CP, Wu J, Liu P, Chen J. 2024. Hepatic progenitor cell-originated ductular reaction facilitates liver fibrosis through activation of hedgehog signaling. Theranostics. 14(6):2379-2395.

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