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Hao Zhu Lab

Research Focus

Regeneration is the scarless replenishment of cell types after acute tissue injury. When injury is persistent, an imperfect regenerative process involving inflammation, mutagenesis, and fibrosis occurs. This process, known as wound healing, is associated with impaired tissue function and cancer. The liver is the ideal system in which to study wound healing. Although the liver is exceptionally regenerative because it evolved to manage toxins and viruses, modern diets and alcohol have overwhelmed its ability to heal, causing an epidemic of liver damage. These chronic injuries cause recurrent cycles of wound healing, culminating in end-stage liver disease, or cirrhosis. Cancers often develop in livers with cirrhosis, illustrating the concept that “cancer is the wound that never heals.”

Using the liver as a model system, our lab is trying to elucidate how injury, regeneration, and wound healing influence organ function and cancer formation. We believe that understanding somatic mosaicism will be a key genetic strategy to deconvolute the complexity of wound healing. In wounds, genetically altered clones are selected for or against based on their contribution to tissue healing. We use human genomic approaches, in vivo genetic screening, and lineage tracing to understand the functional implications of somatic mosaicism in chronic liver disease and liver cancer.

Hao Zhu earned his bachelor’s degree in biology from Duke University, followed by an M.D. from Harvard Medical School and MIT….
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Research Projects

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Wang, Z., Zhu, S., Jia, Y., Wang, Y., Kubota, N., Fujiwara, N., Gordillo, R., Lewis, C., Zhu, M., Sharma, T., Li, L., Zeng, Q., Lin, Y.H., Hsieh, M.H., Gopal, P., Wang, T., Hoare, M., Campbell, P., Hoshida, Y., and H. Zhu. (2023). Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease. Cell 186, 1968-1984. (PubMed)

Lin, Y.H., Wei, Y., Zeng, Q., Wang, Y., Pagani, C.A., Li, L., Zhu, M., Wang, Z., Hsieh, M.H., Corbitt, N., Zhang, Y., Sharma, T., Wang, T., and H. Zhu. (2023). IGFBP2 expressing midlobular hepatocytes preferentially contribute to liver homeostasis and regeneration. Cell Stem Cell 30, 665-676. (PubMed)

Jia, Y., Li, L., Lin, Y.H., Gopal, P., Shen, S., Zhou, K., Yu, X., Sharma, T., Zhang, Y., Siegwart, D., Ready, J., and H. Zhu. (2022). In vivo CRISPR screening identifies BAZ2 chromatin remodelers as druggable regulators of mammalian liver regeneration. Cell Stem Cell 3, 372-385.(PubMed)

Wei, Y., Wang, Y.G., Jia, Y., Li, L., Yoon, J., Zhang, S., Wang, Z., Zhang, Y., Zhu, M., Sharma, T., Lin, Y.H., Hsieh, M.H., Albrecht, J.H., Le, P.T., Rosen, C.J., Wang, T., and H. Zhu. (2021). Liver homeostasis is maintained by midlobular zone 2 hepatocytes. Science 371:eabb162. (PubMed)

Wang, Z., Chen, K., Jia, Y., Chuang, J.C., Sun, X., Lin, Y.H., Celen, C., Li, L., Huang, F., Liu, X., Castrillon, D.H., Wang, T., and H. Zhu. (2020). Dual ARID1A/ARID1B loss leads to rapid carcinogenesis and disruptive redistribution of BAF complexes. Nature Cancer 1, 909–922. (PubMed)

Lin, Y.H., Zhang, S., Zhu, M., Lu, T., Chen, K., Wen, Z., Wang, S., Xiao, G., Luo, D., Jia, Y., Li, L., MacConmara, M., Hoshida, Y., Singal, A., Yopp, A., Wang, T., and H. Zhu.(2020). Mice With Increased Numbers of Polyploid Hepatocytes Maintain Regenerative Capacity But Develop Fewer Hepatocellular Carcinomas Following Chronic Liver Injury. Gastroenterology 158, 1698-1712. (PubMed)

Zhu, M., Lu, T., Jia, Y., Luo, X., Gopal, P., Li, L., Odewole, M., Renteria, V., Singal, A.G., Jang, Y., Ge, K., Wang, S.C., Sorouri, M., Parekh, J.R., MacConmara, M.P., Yopp, A.C., Wang, T., and H. Zhu. (2019). Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease. Cell 177, 608-621. (PubMed)

Zhang, S., Zhou, K., Luo, X., Li, L., Tu, H.C., Sehgal, A., Nguyen, L.H., Zhang, Yu., Gopal, P., Tarlow, B., Siegwart, D.J., and H. Zhu. (2018). The polyploid state plays a tumor-suppressive role in the liver. Developmental Cell 44, 447-459.  (PubMed)

Zhang, S., Nguyen, L.H., Zhou, K., Tu, H.C., Sehgal, A., Nassour, I., Li, L., Gopal, P., Goodman, J.,  Singal, A.G., Yopp, A., Zhang, Y., Siegwart, D.J., and H. Zhu. (2017). Knockdown of Anillin Actin Binding Protein Blocks Cytokinesis in Hepatocytes and Reduces Liver Tumor Development in Mice Without Affecting Regeneration. Gastroenterology 154, 1421-1434. (PubMed)

Sun, X.,* Wang, S.C.,* Luo, X., Jia, Y., Li, L., Gopal, P., Zhu, M., Nassour, I., Chuang, J.C., Maples, T., Celen, C., Nguyen, L.H., Wu, L., Fu, S., Li, W., Hui, L., Tian, F., Ji, Y., Zhang, S., Sorouri, M., Hwang, T.H., Letzig, L., James, L., Yopp, A., Singal, A., and H. Zhu. (2017). Arid1a has context-dependent oncogenic and tumor suppressor functions in liver cancer. Cancer Cell 32, 574-589. (PubMed)

Sun, X., Chuang, J.C., Kanchwala, M., Wu, L., Celen, C., Li, L., Liang, H., Zhang, S., Maples, T., Nguyen, L.H., Wang, S.C., Signer, R.A., Sorouri, M., Nassour, I., Liu, X., Xu, J., Wu, M., Zhao, Y., Kuo, Y.C., Wang, Z., Xing, C., and H. Zhu. (2016). Suppression of the SWI/SNF Component Arid1a Promotes Mammalian Regeneration. Cell Stem Cell 18, 456–466. (PubMed)

Wu, L.,* Nguyen, L.H.,* Zhou, K., Soysa, T.Y., Li, L., Miller, J.B., Tian, J., Locker, J., Zhang, S., Shinoda, G., Seligson, M.T., Zeitels, L.R., Acharya, A., Wang, S.C., Mendell, J.T., He, X., Nishino, J., Morrison, S.J., Siegwart, D.J., Daley, G.Q., Shyh-Chang, N., and H. Zhu. (2015). Precise Let-7 expression levels balance organ regeneration against tumor suppression. eLife 4:e09431. (PubMed)

Nguyen, L.H.,* Robinton, D.A.,* Seligson, M.T.,* Wu, L., Li, L., Rakheja, D., Comerford, S.A., Ramezani, S., Sun, X., Parikh, M.S., Yang, E.H., Powers, J.T., Shinoda, G., Shah, S.P., Hammer, R.E., Daley, G.Q.,# and H. Zhu.# (2014). Lin28b is sufficient to drive liver cancer and necessary for its maintenance in murine models. Cancer Cell 26, 248–261. (PubMed)

*Contributed equally

#Co-corresponding author

Lab Members

Andrew Chung, M.D., Ph.D.

Surgery Residency, Massachusetts General Hospital
M.D./Ph.D Student (2016-2021)

Cemre Celen, Ph.D.

Scientist, Genentech
Grad Student (2015-2020)

Jen-Chien Chuang, Ph.D.

Associate Director, Takeda
Assistant Instructor (2014-2016)

Jason Guo, B.S.

M.D. Student, UTSW
Moody Medical Research Institute Research Specialist (2021-2022)

Yuemeng Jia, B.S.

Postdoctoral Fellow, Harvard
Ph.D. Student (2017-2022)

John Karalis, M.D.

General Surgery Resident, UT Southwestern
General Surgery Fellow (2020-2022)

Yu-Hsuan Lin, Ph.D.

Scientist I, Nkarta
Ph.D. Student (2018-2022)

Ningning Liu, Ph.D.

Assistant Professor, Institute of Microbiology of the Chinese Academy of Sciences
Assistant Instructor (2021-2022)

Tianshi Lu, Ph.D.

Senior Scientist, Genentech
Graduate Student (2017-2021)

Xin Luo, Ph.D.

Senior Scientist, Computational Biologist, Amgen
Data Scientist (2016-2018)

Austin Moore, M.D., Ph.D.

Pediatrics Resident, Boston Children’s Hospital
M.D./Ph.D Student (2016-2021)

Ibrahim Nassour, M.D.

Assistant Professor, Department of Surgery, University of Florida
Clinical Fellow, Surgery (2015-2017)

Liem Nguyen, M.D., Ph.D.

Internal Medicine Resident, University of Washington
Ph.D. Student (2013- 2017)

Shunli Shen, M.D., Ph.D.

Associate Professor, First Affiliated Hospital, Sun Yat-sen University
Visiting Scholar (2018)

XuXu Sun, Ph.D.

Assistant Professor, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University
Postdoctoral Fellow (2013-2019)

Sam Wang, M.D.

Associate Professor, Department of Surgery, UT Southwestern Medical Center
Assistant Professor, Department of Surgery, UT Southwestern Medical Center (2014-2022)

Zixi Wang, Ph.D.

Assistant Professor, Shenzhen Bay Laboratory
Assistant Instructor (2021-2023)

Yonglong Wei, Ph.D.

Assistant Professor, Center for Life Science, Yunnan University
Postdoctoral Fellow (2016-2022)

Linwei Wu, Ph.D.

Associate Professor, First Affiliated Hospital, Sun Yat-sen University
Visiting Scholar (2013–2015)

Shu Xiao, Ph.D.

Senior Research Associate, Department of Surgery, UT Southwestern Medical Center
Senior Research Associate (2018-2022)

Shuyuan Zhang

Postdoctoral Fellow, Stanford University
Ph.D. Student (2013-2018)

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