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.
The cellular basis of liver regeneration has been highly contentious. We generated 12 CreER strains to perform systematic, side-by-side comparisons of hepatocytes in various zones, including populations previously implicated as stem cells (Science 371:eabb1625, 2021). During homeostasis, major differences were found: cells from zones 1 and 3 contracted in number, while cells from midlobular zone 2 (cells expressing Hamp2 and Igfbp2) expanded in number. Hepatocytes in zone 2, which are the most insulated from toxins, also contributed to regeneration after injury (Cell Stem Cell 30, 665-676, 2023). Zone 2 cells are the main source of new hepatocytes before and after injury. Because the distinct metabolic functions of the liver are spatially compartmentalized into zones, there may also be spatial heterogeneity of cell fates in response to cancer driver mutations.
We are currently trying to understand what happens to normal cells that obtain cancer driver mutations and how those cells might progress to cancer. These studies have the potential to reveal new therapeutic strategies based on improved understanding of liver cancer’s zonal or positional origins.
Somatic mosaicism is a new frontier for human genetics and represents an untapped source of disease genes. While somatic mutations can now be identified using deep sequencing, the functional analysis of such mutations remains challenging and will require new approaches. We are currently using in vivo screening and lineage tracing as well as CRISPR technologies to rapidly model the phenotypic impact of somatic mutations. Just as germline sequencing has identified genes that have transformed fields, the discovery of genes that are recurrently mutated in chronically injured tissues but not in cancer has the potential to transform our understanding of regeneration and wound healing.
It is widely assumed that cancer risk increases with regenerative capacity, but we suspect the relationship is more complicated. In mammals, chronic organ damage in the skin, lung, intestine, and liver is strongly associated with cancer, but it is possible that the potent regenerative abilities of these organs serve to preserve tissue integrity, reduce inflammation, and resist transformation in the context of recurrent injury.
Causative mechanisms have been difficult to study because animals with different regenerative capabilities are often evolutionarily or genetically distant. Another strategy is to develop mice with enhanced or altered organ regeneration in order to understand how modulating regeneration influences carcinogenesis in the liver. This work is inspired by the clinical problem of hepatocellular carcinoma (HCC), a malignancy that arises from a highly regenerative organ that experiences recurrent injury. A goal for our lab is to understand how influences on regeneration may be employed to control cancer development.
Zhu, M., Wang, Y., Lu, T., Guo, J., Li, L., Hsieh, M.H., Gopal, P., Han, Y., Fujiwara, N., Wallace, D.P., Yu, A.S.L., Fang, X., Ransom, C., Verschleisser, S., Hsiehchen, D., Hoshida, Y., Singal, A.G., Yopp, A., Wang, T., and H. Zhu. PKD1 mutant clones within cirrhotic livers inhibit steatohepatitis without promoting cancer. (2024). Cell Metabolism 36, 1711-25. (PubMed)
Lim, Y.Z., Zhu, M., Wang, Y., Sharma, T., Kelley, S., Oertling, E., Zhu, H., and N. Corbitt. (2024). Pkd1l1-deficiency drives biliary atresia through ciliary dysfunction in biliary epithelial cells. Journal of Hepatology 81, 62-75. (PubMed)
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)
G. Maggiore and H. Zhu. Relationships Between Regeneration, Wound Healing, and Cancer. (2024). Annual Review of Cancer Biology 8, 177-197. (Link)
Liang, R., Lin, Y.H., and H. Zhu. Genetic and Cellular Contributions to Liver Regeneration. (2021). Cold Spring Harb Perspect Biol 14:a040832. (PubMed)
Zhang, S., Lin, Y.H., Tarlow, B., and H. Zhu. (2019). The origins and functions of hepatic polyploidy. Cell Cycle 18, 1302-1315. (PubMed)
Andrew Chung, M.D., Ph.D.
Cemre Celen, Ph.D.
Jen-Chien Chuang, Ph.D.
Jason Guo, B.S.
Yuemeng Jia, B.S.
John Karalis, M.D.
Yu-Hsuan Lin, Ph.D.
Ningning Liu, Ph.D.
Tianshi Lu, Ph.D.
Xin Luo, Ph.D.
Austin Moore, M.D., Ph.D.
Ibrahim Nassour, M.D.
Liem Nguyen, M.D., Ph.D.
Shunli Shen, M.D., Ph.D.
XuXu Sun, Ph.D.
Sam Wang, M.D.
Zixi Wang, Ph.D.
Yonglong Wei, Ph.D.
Linwei Wu, Ph.D.
Shu Xiao, Ph.D.
Shuyuan Zhang
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Hao Zhu earned his bachelor’s degree in biology from Duke University, followed by an M.D. from Harvard Medical School and MIT. He underwent clinical training in internal medicine at the University of California, San Francisco, and medical oncology at the Dana-Farber Cancer Institute. Dr. Zhu performed postdoctoral research in George Daley’s laboratory at Boston Children’s Hospital from 2008 to 2012. He joined the faculty of Children’s Medical Center Research Institute at UT Southwestern in 2012. Dr. Zhu is the Director of CRI's Tissue Regeneration Program and a co-leader of the Development and Cancer Research Program in the Simmons Comprehensive Cancer Center. As a medical oncologist, he treats hepatocellular carcinoma patients in the Multidisciplinary Liver Cancer Clinic at Parkland Memorial Hospital.
Dr. Zhu is the recipient of a Burroughs Wellcome Career Award for Medical Scientists (2012), a CPRIT Scholar Award (2012), a Stand Up To Cancer Innovative Research Grant (2016), and the Mark Foundation Emerging Leader Award (2021). Dr. Zhu holds the Nancy B. and Jake L. Hamon Distinguished Chair in Therapeutic Oncology Research.
