Xianfang Wu Laboratory

Research

Current Projects

1. For decades, stem cells and other primitive cells have been recognized for their resistance to viral infections, particularly retroviruses. Recent studies have extended these observations across a wide variety of viruses and tissue stem cells, suggesting that virus resistance is a general property of stem cells. This resistance likely evolved to protect these critical cells, given their essential roles in tissue regeneration and repair. While eukaryotic cells have developed numerous strategies to defend against pathogens, stem cells are unique in that they do not mount the same robust interferon (IFN) responses that terminally differentiated cells rely on to combat infections. As a result, the specific mechanisms by which stem cells effectively block viral infection remain poorly understood.

Our recent study revealed that stem cells constitutively express a subset of IFN-stimulated genes (ISGs) independently of IFN signaling. This intrinsic ISG expression is cell-type specific and diminishes as cells undergo terminal differentiation, at which point they become responsive to traditional IFN signaling pathways. We also demonstrated that intrinsically expressed ISGs protect stem cells from viral infection both in vitro and in vivo (Wu et al. Cell. 2018; et al. Current opinion in immunology. 2019). However, the regulatory mechanisms driving this intrinsic ISG expression in stem cells remain unclear. To address this, we will employ comprehensive and unbiased approaches, such as RNA-seq, ATAC-seq, and CRISPR knockout screens, to dissect the regulatory mechanisms controlling intrinsic ISG expression in stem cells. This research is supported by an NIH K99/R00 grant (5R00AI141742).

2. Mechanistic insights into human disease can facilitate the development of treatments that are effective across broad patient populations. Traditionally, human diseases have been studied using preclinical models, which have enabled numerous powerful research avenues. However, recent advances in human pluripotent stem cell (hPSC, including hESC and iPSC) technology, combined with new genomic editing and mutagenesis tools, have opened exciting opportunities for human disease modeling. These advances are particularly valuable for studying diseases associated with genetic variations, offering the potential for personalized and precise identification of drug targets and biomarkers to improve clinical outcomes. In this project, we will focus on developing multicellular models, including organoid cultures and 3D Transwell cultures, to better understand fibrotic liver diseases, such as alcoholic and nonalcoholic fatty liver diseases (Park et al. Journal of Hepatology. 2023), as well as liver diseases caused by viral infections and excessive alcohol drinking. This work is supported by the NIH Director's New Innovator Award (DP2) (1DP2AI170515), NIH R03 grant (NCATS, 1R03TR004584) NIH R01 grant (NIAAA 1R01AA031226).

Selected Publications

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) 

33. Lin W, Szabo C, Liu T, Tao H, Wu X, Wu J. STING trafficking activates MAPK–CREB signaling to trigger regulatory T cell differentiation. Proc Natl Acad Sci USA. July 10, 2024. 121 (29) e2320709121

34. Chi H, Qu B, Prawira A, Richardt T, Maurer L, Hu J, Fu RM, Lempp FA, Zhang Z, Grimm D, Wu X, Urban S, Dao Thi VT. An Hepatitis B and D Virus Infection Model Using Human Pluripotent Stem Cell-Derived Hepatocyte-Like Cells for Virus Host Interactions and Antiviral Evaluation. EMBO Reports (In press).