Yumin Oh1,2,10, Ogyi Park1,2,3,10, Magdalena Swierczewska1,2,10, James P. Hamilton,4 Jong-Sung Park1,2, Tae Hyung Kim1,2, Sung-Mook Lim5, Hana Eom5, Dong Gyu Jo5, Choong-Eun Lee6, Raouf Kechrid3, Panagiotis Mastorakos2, Clark Zhang2, Sei Kwang Hahn7, Ok-Cheol Jeon8, Youngro Byun8, Kwangmeyung Kim9, Justin Hanes2, Kang Choon Lee5, Martin G. Pomper1, Bin Gao3,* and Seulki Lee1,2,*
1The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 2The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 3Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA 4Divison of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 5College of Pharmacy, Sungkyunkwan University, Suwon, Korea 6Department of Biological Science, Sungkyunkwan University, Suwon, Korea 7Department of Materials Science and Engineering, Pohang University of Science and Technology, Pohang, Korea 8College of Pharmacy, Seoul National University, Seoul, Korea 9Center for Theragnosis, Korea Institute of Science and Technology, Seoul, Korea 10These authors contributed equally to this work.
* Correspondence authors: Bin Gao, M.D., Ph.D., Laboratory of Liver Diseases, NIAAA/NIH, 5625 Fishers Lane, Bethesda, MD 20892. and Seulki Lee, Ph.D. The Russell H. Morgan Department of Radiology and Radiological Sciences, The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University, School of Medicine, Baltimore, MD 21231.
Liver fibrosis is a common outcome of chronic liver disease and leads to liver cirrhosis and hepatocellular carcinoma. No FDA-approved targeted anti-fibrotic therapy exists. Activated hepatic stellate cells (aHSCs) are the major cell types responsible for liver fibrosis; therefore, eradication of aHSCs, while preserving quiescent HSCs and other normal cells, is a logical strategy to stop and/or reverse liver fibrogenesis/fibrosis. However, there are no effective approaches to specifically deplete aHSCs during fibrosis without systemic toxicity. aHSCs are associated with elevated expression of death receptors (DRs) and become sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death. Treatment with recombinant TRAIL could be a potential strategy to ameliorate liver fibrosis; however, the therapeutic application of recombinant TRAIL is halted due to its very short half-life. To overcome this problem, we previously generated PEGylated TRAIL (TRAILPEG) that has a much longer half-life in rodents than native-type TRAIL. Here, we demonstrate that intravenous TRAILPEG has a markedly extended half-life over native-type TRAIL in non-human primates and has no toxicity in primary human hepatocytes. Intravenous injection of TRAILPEG directly induces apoptosis of aHSCs in vivo and ameliorates carbon tetrachloride-induced fibrosis/cirrhosis in rats by simultaneously down-regulating multiple key fibrotic markers that are associated with aHSCs. In conclusion, TRAIL-based therapies could serve as new therapeutics for liver fibrosis/cirrhosis and possibly other fibrotic diseases. This article is protected by copyright. All rights reserved.
Keywords: apoptosis, cirrhosis, death receptors, fibrosis, hepatic stellate cells, TRAIL