title: Adenoviral delivery of truncated MMP-8 fused with the hepatocyte growth factor mutant 1K1 ameliorates liver cirrhosis and promotes hepatocyte proliferation.
abstract: Liver cirrhosis is a chronic liver disease caused by chronic liver injury, which activates hepatic stellate cells (HSCs) and the secretion of extracellular matrix (ECM). Cirrhosis accounts for an extensive level of morbidity and mortality worldwide, largely due to lack of effective treatment options. In this study, we have constructed a fusion protein containing matrix metal-loproteinase 8 (MMP-8) and the human growth factor mutant 1K1 (designated cMMP8-1K1) and delivered it into hepatocytes and in vivo and in cell culture via intravenous injection of fusion protein-harboring adenovirus. In doing so, we found that the cMMP8-1K1 fusion protein promotes the proliferation of hepatocytes, likely resulting from the combined inhibition of type I collagen secretion and the degradation of the ECM in the HSCs. This fusion protein was also observed to ameliorate liver cirrhosis in our mouse model. These changes appear to be linked to changes in downstream gene expression. Taken together, these results suggest a possible strategy for the treatment of liver cirrhosis and additional work is warranted.
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pathology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong, People's Republic of China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Fu
authors.affiliation: Key Lab of Surgery of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
authors.forename: Jiacheng
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
authors.forename: Xu
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
authors.forename: Yuelong
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
authors.forename: Ren'an
authors.initials: R
authors.lastname: Jin
authors.affiliation: Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.
authors.forename: Anyong
authors.initials: A
authors.lastname: Xie
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China ; Key Lab of Surgery of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
authors.forename: Xiujun
authors.initials: X
authors.lastname: Cai
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D002251:Carbon Tetrachloride; D020134:Catalytic Domain; D049109:Cell Proliferation; D024042:Collagen Type I / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D057809:HEK293 Cells; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D022781:Hepatocytes / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008115:Liver Regeneration; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000096:biosynthesis* / Q000235:genetics; D008807:Mice, Inbred BALB C; D009154:Mutation; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014162:Transfection
chemical_list: D024042:Collagen Type I; C066855:HGF protein, human; D011993:Recombinant Fusion Proteins; D017228:Hepatocyte Growth Factor; D002251:Carbon Tetrachloride; D020784:Matrix Metalloproteinase 8
keywords: HGF; MMP-8; hepatocytes proliferation; liver cirrhosis