Location: Cleveland Clinic Main Campus
Our laboratory at Cleveland Clinic focuses on two main directions: 1) understanding the intrinsic differences in antiviral resistance between stem cells and terminally differentiated cells; and 2) modeling human disease using stem cell-derived multicellular culture systems. Currently we are interested in metabolic liver disease (e.g., non-alcoholic fatty liver disease and alcoholic liver disease) and infection by hepatitis viruses (e.g., hepatitis B virus and hepatitis C virus).
Ph.D: Florida State University (Thesis advisor: Dr. Hengli Tang)
Post-doctoral training: Rockefeller University (Mentor: Dr. Charles M. Rice)
(1). For many decades, stem cells and other primitive cells have been known to resist virus infection, particularly retroviruses. Recent studies have made similar observations with a diverse array of viruses and tissue stem cells, suggesting that virus resistance is a general property of stem cells. Such restriction likely evolved to protect these primitive cells because of their critical roles in tissue regeneration and repair. Eukaryotic cells have evolved multiple strategies to protect themselves against pathogens. Stem cells, however, are unique. When exposed to pathogens they do not produce the same robust interferon (IFN) responses that terminally differentiated cells use to combat infection. Therefore, the mechanisms by which stem cells potently block virus infection are poorly understood.
Our recent study revealed that stem cells constitutively express subset of IFN stimulated genes (ISGs), independently of IFNs. This intrinsic ISG expression varies in a cell type-specific manner and ISG expression decreases as cells terminally differentiate at which time cells become responsive to canonical IFN signaling. We also demonstrated that intrinsically expressed ISGs protect stem cells against viral infection in vitro and in vivo. The mechanisms underlying this intrinsic ISG expression in stem cells, however, remain elusive. To this end, we will use comprehensive and less biased approaches (e.g. RNA-seq, ATAC-seq, CRISPR KO screens) to dissect the regulatory mechanisms governing intrinsic ISG expression in stem cells. This work is supported by NIH K99/R00 grant (5R00AI141742)
(2). Mechanistic insights into human disease may enable the development of treatments that are effective in broad patient populations. Traditionally, human diseases have been studied in preclinical models, which enable many powerful avenues for research. Recently, the emergence and marriage of ex vitro human pluripotent stem cells (hPSCs, including hESC and iPSCs)-based human tissue engineering technologies and new powerful tools for genomic editing/mutagenesis have offered new opportunities for human disease modeling and deep biological understanding, especially for diseases that are associated with genetic variations, promising the personalized/precise identification of drug targets and biomarkers for improving clinical practice. In this project, we will be focusing on developing multicellular models (organoid culture and 3D Transwell culture) to understand fibrotic liver diseases, including alcoholic and nonalcoholic fatty liver diseases, and diseases caused by viral infection. This work is supported by NIH Director's New Innovator Award (DP2) (1DP2AI170515)
View publications for Xianfang Wu, PhD
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1. Zhou Y, Wu X, Qu W, Wang X. Study on the method for determination of pentachlorophenol in water, Journal of Hygiene Research. 2007 May; 36(3):287-8.
2. Wu X, Wang S, Pan T, Yi Z, Yuan Z. Viperin protein inhibits hepatitis C virus replication partially through disturbing the association of nonstructural proteins with lipid rafts. Journal of Microbes and Infections, 2009, Dec; 4(4): 203-208.
3. Yi Z, Pan T, Wu X, Song W, Wang S, Xu Y, Rice CM, Macdonald MR, Yuan Z.. Hepatitis C virus co-opts Ras-GTPase-activating protein-binding protein 1 (G3BP1) for its genome replication, Journal of Virology. 2011 Jul;85(14):6996-7004.
4. Liang Q, Deng H, Li X, Wu X, Tang Q, Chang TH, Peng H, Rauscher FJ 3rd, Ozato K, Zhu F. Tripartite motif-containing protein 28 is a small ubiquitin-related modifier E3 ligase and negative regulator of IFN regulatory factor 7. Journal of Immunology. 2011 Nov. 1;187(9):4754-63.
5. Wang S*, Wu X*, Pan T, Song W, Wang Y, Zhang F, Yuan Z. Viperin inhibits hepatitis C virus replication by interfering with binding of NS5A to host protein hVAP-33. Journal of General Virology. 2012 Jan;93(Pt 1):83-92. (* co-first author)
6. Wu X, Robotham JM, Lee E, Dalton S, Kneteman NM, Gilbert DM, Tang H. Productive Hepatitis C Virus Infection of Stem Cell-Derived Hepatocytes Reveals a Critical Transition to Viral Permissiveness during Differentiation. PLoS Pathogens. 2012;8(4):e1002617.
7. Jiang J, Cun W, Wu X, Shi Q, Tang H, Luo G. Hepatitis C virus attachment mediated by apolipoprotein E binding to cell surface heparan sulfate. Journal of Virology. 2012 Jul;86(13):7256-67.
8. Jiang J, Wu X, Tang H, Luo G.. Apolipoprotein E Mediates Attachment of Clinical Hepatitis C Virus to Hepatocytes by Binding to Cell Surface Heparan Sulfate Proteoglycan Receptors. PLoS One. 2013 Jul 2;8(7):e67982.
9. Wu X, Lee EM, Hammack C, Robotham JM, Basu M, Lang J, Brinton MA, Tang H. Cell death-inducing DFFA-like effector b is required for hepatitis C virus entry into hepatocytes. Journal of Virology. 2014 Aug;88(15):8433-44.
10. VLD Thi, Y Debing, X Wu, CM Rice, J Neyts, D Moradpour, J Gouttenoire. Sofosbuvir inhibits hepatitis E virus replication in vitro and results in an additive effect when combined with Ribavirin. Gastroenterology. 2015 Sep 25. pii: S0016-5085(15)01355-4.
11. Lee EM, Alsagheir A, Wu X, Hammack C, McLauchlan J, Watanabe N, Wakita T, Kneteman NM, Douglas DN, Tang H. Hepatitis C virus induced degradation of cell death-inducing DFFA-like effector B leads to hepatic lipid dysregulation. Journal of Virology. 2016 Mar 28;90(8):4174-85.
12. VL Dao Thi, Y Debing, X Wu, CM Rice, J Neyts, D Moradpour, J Gouttenoire. Targeting Viral Polymerase for Treating Hepatitis E Infection: How Far Are We? Reply. Gastroenterology. 2016, Jun 150 (7): 1690-1691
13. Luna JM, Wu X, Rice CM. Present and not reporting for duty: dsRNAi in mammalian cells. EMBO Journal. 2016, Dec 35 (23): 2499-2501
14. Xiang K, Michailidis E, Ding H, Peng Y, Su M, Liu X, VLD Thi, Wu X, Schneider W, Rice C, Zhuang H, and Li T. Effects of amino acid substitutions in hepatitis B virus surface protein on virion secretion, antigenicity, HBsAg and viral DNA. Journal of Hepatology. 2017 Feb;66(2):288-296.
15. Takacs CN, Andreo U, Dao Thi VL, Wu X, Gleason CE, Itano MS, Spitz G, Belote RL, Flatley BR, Scull MA, Rice CM and Simon SM. Differential regulation of lipoprotein and hepatitis C virus secretion by Rab1b. Cell Reports. 2017 Oct 10;21(2):431-441.
16. Wu X*, Dao Thi VL*, Liu P, Takacs C, Xiang K, Andrus L, Gouttenoire J, Moradpour D, and Rice C. Pan-Genotype Hepatitis E virus Replication in Stem Cell-derived Hepatocellular Systems. Gastroenterology. 2018, Feb 154 (3): 663-674 (* co-first author)
17. Wu X, Dao Thi VL, Huang Y, Billerbeck E, Saha D, Hoffmann H-H, Wang Y, Vale Silva, LA, Sarbanes S, Sun T, Andrus L, Yu Y, Quirk C, Li M, MacDonald MR, Schneider WM, An X, Rosenberg B, and Rice CM. Intrinsic Immunity Shapes Viral Resistance of Stem Cells. Cell. 2018, Jan 172: 423-438.
18. Chung H, Calis JA, Wu X, Sun T, Yu Y, Sarbenes SL, Dao Thi, VL, Shilvock, AR, Hoffmann, HH, Rosenberg, BR, Rice CM. Human ADAR1 prevents endogenous RNA from triggering translational shutdown. Cell. 2018, Feb 172: 811-824
19. Wu X*, Dao Thi VL*. ES/iPC-derived hepatocellular systems for HCV culture. Third Edition on Hepatitis C Virus Protocols, Methods in Molecular Biology (Springer). (* co-corresponding author)
20. Wu X, Kwong AC, Rice CM. Antiviral resistance of stem cells. Current Opinion in Immunology. 2018 Oct 20; 56:50-59.
21. Dao Thi VL*, Wu X*, Rice CM*. Stem cell-derived culture models of HEV infection. Enteric Hepatitis Viruses. Cold Spring Harbor Perspectives in Medicine. 2019 Mar 1;9(3):a031799. (* co-corresponding author)
22. Li W, Wang Y, Zhao H, Zhang H, Xu Y, Wang S, Guo X, Huang Y, Zhang S, Han Y, Wu X, Rice CM, Huang G, Gallagher PG, Mendelson A, Yazdanbakhsh K, Liu J, Chen L, An X. Identification and transcriptome analysis of erythroblastic island macrophages. Blood. 2019 134:480-491.
23. Li MMH, Anguilar EG, Michailidis E, Pabon J, Park P, Wu X, de Jong YP, Schneider WM, Molina H, Rice CM, and MacDonald MR. Characterization of novel splice variants of zinc finger antiviral protein (ZAP). Journal of Virology. 2019 Aug 28; 93(18). pii: e00715-19.
24. Basak A, Munschauer M, Lareau CA, Montbleau KE, Ulirsch JC, Hartigan CR, Schenone M, Lian J, Wang Y, Huang Y, Wu X, Gehrke L, Rice CM, An X, Christou HA, Mohandas A, Carr SA, Chen J-J, Orkin SH, Lander ES, and Sankaran VG. Control of human hemoglobin switching by LIN28B-mediated regulation of BCL11A translation. Nature Genetics. 52, 138–145(2020).
25. Dao Thi VL#, Wu X#, Belote R, Andreo U, Takacs C, Vale-Silva LA, Prallet S, Uryu K, Fernandes JP, Molina H, Saeed, M, Steinmann E, Signaraja RR, Schneider WM, Simon SM, Rice CM#. Stem cell-derived polarized hepatocyte. Nature Communications. 2020. 11 (1), 1-13 (#co-corresponding authors).
26. Saeed M, Kapell S, Hertz NT, Wu X, Bell K, Ashbrook, AW, Mark MT, Zebroski HA, Neal M, Flodstrom-Tullberg M, MacDonald MR, Aitchison JD, Molina H, Rice CM. Defining the proteolytic landscape during enterovirus infection. PLoS Pathogens. 2020:16(9): e1008927.
27. Hoffmann H-H, Schneider WM, Rozen-Gagnon R, Miles, LA, Schuster F, Razooky, B, Jacobson E, Wu X, Yi S, Rudin CM, MacDonald, MR, McMulian LK, Poirier JT, Rice CM. TMEM41B is a pan-dlavivirus host factor. Cell. 184 (1), 133-148. e20
28. Sun T, Yu Y, Wu X, Acevedo A, Luo, J, Wang J, Schneider WM, Hurwitz, BS, Rosenberg, BR, Chung, H, Rice CM. Decoupling expression and editing preferences of ADAR1 p150 and p110 isoforms. Proc Natl Acad Sci USA. March 23, 2021 118 (12) e2021757118
29. Bushweller L, Zhao Y, Zhang F, Wu X*. Generation of Human Pluripotent Stem Cell-derived Polarized Hepatocytes. Current Protocols. 2022 Jan;2(1):e345
30. Park J, Zhao Y, Zhang F, Zhang S, Kwong AC, Zhang Y, Hoffmann H-H, Bushweller L, Wu X, Ashbrook AW, Stefanovic B, Chen S, Branch AD, Mason CE, Jung JU, Rice CM, and Wu X*. The IL6/STAT3 axis dictates the PNPLA3-mediated susceptibility to nonalcoholic fatty live disease. Journal of Hepatology. 2023 Jan;78(1):45-56.
31. Y Sun, X Li, C Yin, J Zhang, E Liang, X Wu, Y Ni, J Arbesman, CR Goding, S Chen. AMPK phosphorylates ZDHHC13 to increase MC1R activity and suppress melanomagenesis. Cancer Research. 2023 Jan 26;CAN-22-2595.
32. Y Yu, WM Schneider, MA Kass, E Michailidis, A Acevedo, ALP Mosimann, J Bordignon, Alexander Koenig, Christine M. Livingston, Hardeep van Gijzel, Yi Ni, Pradeep M. Ambrose, CA Freije, M Zhang, C Zou, M Kabbani, C Quirk, C Jahan, X Wu, S Urban, S You, A Shlomai, YP de Jong, CM Rice. An RNA-based system to study hepatitis B virus replication and evaluate antivirals. Science Advances. 2023 (In press)