Cholangiocyte-Derived Exosomal Long Noncoding RNA H19 Promotes Hepatic Stellate Cell Activation and Cholestatic Liver Fibrosis

被引：198

作者：

Liu, Runping ^{[1
,2
,3
]}

Li, Xiaojiaoyang ^{[1
,2
,3
]}

Zhu, Weiwei ^{[1
,2
,4
]}

Wang, Yanyan ^{[1
,2
,5
]}

Zhao, Derrick ^{[1
,2
,3
]}

Wang, Xuan ^{[1
,2
,3
]}

Gurley, Emily C. ^{[1
,2
,3
]}

Liang, Guang ^{[4
]}

Chen, Weidong ^{[5
]}

Lai, Guanhua ^{[6
]}

Pandak, William M. ^{[2
,3
]}

Lippman, H. Robert ^{[7
]}

Bajaj, Jasmohan S. ^{[2
,3
]}

Hylemon, Phillip B. ^{[1
,2
,3
]}

Zhou, Huiping ^{[1
,2
,3
]}

机构：

[1] Virginia Commonwealth Univ, Dept Microbiol & Immunol, 1220 East Broad St,MMRB 5044, Richmond, VA 23298 USA

[2] Virginia Commonwealth Univ, McGuire Vet Affairs Med Ctr, 1220 East Broad St,MMRB 5044, Richmond, VA 23298 USA

[3] Virginia Commonwealth Univ, Div Gastroenterol Hepatol & Nutr, Richmond, VA 23298 USA

[4] Wenzhou Med Univ, Sch Pharmaceut Sci, Wenzhou, Zhejiang, Peoples R China

[5] Anhui Univ Chinese Med, Sch Pharmaceut Sci, Hefei, Anhui, Peoples R China

[6] Virginia Commonwealth Univ, Dept Pathol, Med Coll, Virginia Campus, Richmond, VA USA

[7] McGuire Vet Affairs Med Ctr, Dept Pathol & Lab Med, Richmond, VA USA

来源：

HEPATOLOGY | 2019年 / 70卷 / 04期

关键词：

GENE-EXPRESSION; PROLIFERATION; MECHANISMS; INJURY; TRANSMISSION; MICRORNAS; DELIVERY; SIRNA; ACID;

D O I：

10.1002/hep.30662

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Activation of hepatic stellate cells (HSCs) represents the primary driving force to promote the progression of chronic cholestatic liver diseases. We previously reported that cholangiocyte-derived exosomal long noncoding RNA-H19 (lncRNA-H19) plays a critical role in promoting cholestatic liver injury. However, it remains unclear whether cholangiocyte-derived lncRNA-H19 regulates HSC activation, which is the major focus of this study. Both bile duct ligation (BDL) and Mdr2 knockout (Mdr2(-/-)) mouse models were used. Wild-type and H19(maternal Delta Exon1/+ )(H19KO) mice were subjected to BDL. Mdr2(-/-)H19(maternal Delta Exon1/+) (DKO) mice were generated. Exosomes isolated from cultured mouse and human cholangiocytes or mouse serum were used for in vivo transplantation and in vitro studies. Fluorescence-labeled exosomes and flow cytometry were used to monitor exosome uptake by hepatic cells. Collagen gel contraction and bromodeoxyuridine assays were used to determine the effect of exosomal-H19 on HSC activation and proliferation. Mouse and human primary sclerosing cholangitis (PSC)/primary biliary cholangitis (PBC) liver samples were analyzed by real-time PCR, western blot analysis, histology, and immunohistochemistry. The results demonstrated that hepatic H19 level was closely correlated with the severity of liver fibrosis in both mouse models and human patients with PSC and PBC. H19 deficiency significantly protected mice from liver fibrosis in BDL and Mdr2(-/-) mice. Transplanted cholangiocyte-derived H19-enriched exosomes were rapidly and preferentially taken up by HSCs and HSC-derived fibroblasts, and promoted liver fibrosis in BDL-H19KO mice and DKO mice. H19-enriched exosomes enhanced transdifferentiation of cultured mouse primary HSCs and promoted proliferation and matrix formation in HSC-derived fibroblasts. Conclusion: Cholangiocyte-derived exosomal H19 plays a critical role in the progression of cholestatic liver fibrosis by promoting HSC differentiation and activation and represents a potential diagnostic biomarker and therapeutic target for cholangiopathies.

引用

页码：1317 / 1335

页数：19

共 46 条

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