University of Pittsburgh Department of Cell Biology

  • Research

    During regeneration, hepatocytes can be derived from either preexisting hepatocytes or biliary epithelial cells (BECs). When hepatocyte-driven liver regeneration is compromised, which is the case in chronic liver diseases, BEC-driven liver regeneration takes place. Understanding the molecular mechanisms of this BEC-driven liver regeneration should provide significant insights into how to promote innate liver regeneration in patients with severe liver diseases as therapeutics. We have established several innovative zebrafish liver regeneration models in which BECs extensively give rise to hepatocytes. Using these models, we have taken several approaches to better understand the mechanisms of BEC-driven liver regeneration, including chemical screening and RNAseq analyses. Currently, we investigate how (1) epigenetic factors, (2) metabolism, and (3) FGFR signaling regulate BEC-driven liver regeneration.

    Upon severe biliary damage, hepatocytes transdifferentiate into BECs, similar to BEC conversion to hepatocytes in the settings of severe hepatocyte damage. We recently developed two zebrafish models for hepatocyte-to-BEC transdifferentiation. Using these models, we investigate the molecular mechanisms underlying this plasticity.


  • Publications

    1. Rizvi F, Lee YR, Diaz-Aragon R, Bawa PS, So J, Florentino RM, Wu S, Sarjoo A, Truong E, Smith AR, Wang F, Everton E, Ostrowska A, Jung K, Tam Y, Muramatsu H, Pardi N, Weissman D, Soto-Gutierrez A, Shin D, Gouon-Evans V. VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis.. Cell Stem Cell. 2023 Dec 7;30(12):1640-1657.e8. doi: 10.1016/j.stem.2023.10.008. PubMed PMID: 38029740;
    2. Lee SH, So J, Shin D. Hepatocyte-to-cholangiocyte conversion occurs through transdifferentiation independently of proliferation in zebrafish.. Hepatology. 2023 Apr 1;77(4):1198-1210. doi: 10.1097/HEP.0000000000000016. PubMed PMID: 36626626;
    3. Jung K, Kim M, So J, Lee SH, Ko S, Shin D. Farnesoid X Receptor Activation Impairs Liver Progenitor Cell-Mediated Liver Regeneration via the PTEN-PI3K-AKT-mTOR Axis in Zebrafish.. Hepatology. 2021 Jul;74(1):397-410. doi: 10.1002/hep.31679. PubMed PMID: 33314176;
    4. So J, Kim A, Lee SH, Shin D. Liver progenitor cell-driven liver regeneration.. Exp Mol Med. 2020 Aug;52(8):1230-1238. doi: 10.1038/s12276-020-0483-0. PubMed PMID: 32796957;
    5. So J, Kim M, Lee SH, Ko S, Lee DA, Park H, Azuma M, Parsons MJ, Prober D, Shin D. Attenuating the Epidermal Growth Factor Receptor-Extracellular Signal-Regulated Kinase-Sex-Determining Region Y-Box 9 Axis Promotes Liver Progenitor Cell-Mediated Liver Regeneration in Zebrafish.. Hepatology. 2021 Apr;73(4):1494-1508. doi: 10.1002/hep.31437. PubMed PMID: 32602149;
    6. Ko S, Russell JO, Tian J, Gao C, Kobayashi M, Feng R, Yuan X, Shao C, Ding H, Poddar M, Singh S, Locker J, Weng HL, Monga SP, Shin D. Hdac1 Regulates Differentiation of Bipotent Liver Progenitor Cells During Regeneration via Sox9b and Cdk8.. Gastroenterology. 2019 Jan;156(1):187-202.e14. doi: 10.1053/j.gastro.2018.09.039. PubMed PMID: 30267710;
    7. So J, Khaliq M, Evason K, Ninov N, Martin BL, Stainier DYR, Shin D. Wnt/β-catenin signaling controls intrahepatic biliary network formation in zebrafish by regulating notch activity.. Hepatology. 2018 Jun;67(6):2352-2366. doi: 10.1002/hep.29752. PubMed PMID: 29266316;
    8. Choi TY, Khaliq M, Tsurusaki S, Ninov N, Stainier DYR, Tanaka M, Shin D. Bone morphogenetic protein signaling governs biliary-driven liver regeneration in zebrafish through tbx2b and id2a.. Hepatology. 2017 Nov;66(5):1616-1630. doi: 10.1002/hep.29309. PubMed PMID: 28599080;
    9. Ko S, Choi TY, Russell JO, So J, Monga SPS, Shin D. Bromodomain and extraterminal (BET) proteins regulate biliary-driven liver regeneration.. J Hepatol. 2016 Feb;64(2):316-325. doi: 10.1016/j.jhep.2015.10.017. PubMed PMID: 26505118;
    10. Choi TY, Ninov N, Stainier DY, Shin D. Extensive conversion of hepatic biliary epithelial cells to hepatocytes after near total loss of hepatocytes in zebrafish.. Gastroenterology. 2014 Mar;146(3):776-88. doi: 10.1053/j.gastro.2013.10.019. PubMed PMID: 24148620;

     

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