Junlai Liu1,2,3, Xiao Hu2, Jie Chen4, Xinqi Li1,2,3, Lu Wang1, Binbin Wang1,2,3, Wenbo Peng1,2,3, Cuiwei Yang1,2,3, Zhijie Li1,2,3, Yan Chen5, Yue J Wang6, Chuanjiang Li5, Xiajun Li1, Fang Yan7, Yunfang Wang7, Changzhen Shang4, Xin Wang8,9,10, Tao Chen4, Pengyu Huang1. 1. School of Life Science and Technology, ShanghaiTech University, Shanghai, China. 2. Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. 3. University of Chinese Academy of Sciences, Beijing, China. 4. Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. 5. Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China. 6. Department of Medicine, Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA. 7. Stem Cell and Tissue Engineering Lab, Beijing Institute of Transfusion Medicine, Beijing, China. 8. The Key Laboratory of National Education Ministry for Mammalian Reproductive Biology and Biotechnology, Inner Mongolia University, Huhhot, P.R. China. 9. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, MN. 10. Hepatoscience Incorporation, Sunnyvale, CA.
Abstract
Liver regeneration (LR) happens after various types of injuries. Unlike the well-studied LR caused by partial hepatectomy (PHx), there is accumulating evidence suggesting that LR during other injuries may result from unknown mechanisms. In this study, we found that insulin-like growth factor 2 (IGF-2) was drastically induced following the liver injuries caused by tyrosinemia or long-term treatments of CCl4 . However, this was not observed during the early phase of acute liver injuries after PHx or single treatment of CCl4 . Remarkably, most IGF-2-expressing hepatocytes were located at the histological area around the central vein of the liver lobule after the liver injuries caused either in fumarylacetoacetate hydrolase-deficient mice or in CCl4 chronically treated mice. Hepatocyte proliferation in vivo was significantly promoted by induced IGF-2 overexpression, which could be inhibited by adeno-associated virus-delivered IGF-2 short hairpin RNAs or linsitinib, an inhibitor of IGF-2 signaling. Proliferating hepatocytes in vivo responded to IGF-2 through both insulin receptor and IGF-1 receptor. IGF-2 also significantly promoted DNA synthesis of primary hepatocytes in vitro. More interestingly, the significantly induced IGF-2 was also found to colocalize with glutamine synthetase in the region enriched with proliferating hepatocytes for the liver samples from patients with liver fibrosis. CONCLUSION: IGF-2 is produced by pericentral hepatocytes to promote hepatocyte proliferation and repair tissue damage in the setting of chronic liver injury, which is distinct from the signaling that occurs post-PHx. (Hepatology 2017;66:2002-2015).
Liver regeneration (LR) happens after various types of injuries. Unlike the well-studied LR caused by partial hepatectomy (PHx), there is accumulating evidence suggesting that LR during other injuries may result from unknown mechanisms. In this study, we found that insulin-like growth factor 2 (IGF-2) was drastically induced following the liver injuries caused by tyrosinemia or long-term treatments of CCl4 . However, this was not observed during the early phase of acute liver injuries after PHx or single treatment of CCl4 . Remarkably, most IGF-2-expressing hepatocytes were located at the histological area around the central vein of the liver lobule after the liver injuries caused either in fumarylacetoacetate hydrolase-deficient mice or in CCl4 chronically treated mice. Hepatocyte proliferation in vivo was significantly promoted by induced IGF-2 overexpression, which could be inhibited by adeno-associated virus-delivered IGF-2 short hairpin RNAs or linsitinib, an inhibitor of IGF-2 signaling. Proliferating hepatocytes in vivo responded to IGF-2 through both insulin receptor and IGF-1 receptor. IGF-2 also significantly promoted DNA synthesis of primary hepatocytes in vitro. More interestingly, the significantly induced IGF-2 was also found to colocalize with glutamine synthetase in the region enriched with proliferating hepatocytes for the liver samples from patients with liver fibrosis. CONCLUSION:IGF-2 is produced by pericentral hepatocytes to promote hepatocyte proliferation and repair tissue damage in the setting of chronic liver injury, which is distinct from the signaling that occurs post-PHx. (Hepatology 2017;66:2002-2015).
Authors: Eleanor L Watts; Aurora Perez-Cornago; Paul N Appleby; Demetrius Albanes; Eva Ardanaz; Amanda Black; H Bas Bueno-de-Mesquita; June M Chan; Chu Chen; S A Paul Chubb; Michael B Cook; Mélanie Deschasaux; Jenny L Donovan; Dallas R English; Leon Flicker; Neal D Freedman; Pilar Galan; Graham G Giles; Edward L Giovannucci; Marc J Gunter; Laurel A Habel; Christel Häggström; Christopher Haiman; Freddie C Hamdy; Serge Hercberg; Jeff M Holly; Jiaqi Huang; Wen-Yi Huang; Mattias Johansson; Rudolf Kaaks; Tatsuhiko Kubo; J Athene Lane; Tracy M Layne; Loic Le Marchand; Richard M Martin; E Jeffrey Metter; Kazuya Mikami; Roger L Milne; Howard A Morris; Lorelei A Mucci; David E Neal; Marian L Neuhouser; Steven E Oliver; Kim Overvad; Kotaro Ozasa; Valeria Pala; Claire H Pernar; Michael Pollak; Mari-Anne Rowlands; Catherine A Schaefer; Jeannette M Schenk; Pär Stattin; Akiko Tamakoshi; Elin Thysell; Mathilde Touvier; Antonia Trichopoulou; Konstantinos K Tsilidis; Stephen K Van Den Eeden; Stephanie J Weinstein; Lynne Wilkens; Bu B Yeap; Timothy J Key; Naomi E Allen; Ruth C Travis Journal: Int J Cancer Date: 2019-04-04 Impact factor: 7.396