Adenoviral delivery of truncated MMP-8 fused with the hepatocyte growth factor mutant 1K1 ameliorates liver cirrhosis and promotes hepatocyte proliferation

Jinghua Liu,1 Jianbo Li,1 Weiwei Fu,2 Jiacheng Tang,3 Xu Feng,1 Jiang Chen,1 Yuelong Liang,1 Ren’an Jin,1 Anyong Xie,4 Xiujun Cai1,31Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, 2Department of Pathology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong, 3Key Lab of Surgery of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, 4SirRun Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of ChinaAbstract: 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 metalloproteinase 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 typeI 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.Keywords: liver cirrhosis, MMP-8, HGF, hepatocytes proliferation