PUBLICATION

Hepatocyte-to-cholangiocyte conversion occurs through transdifferentiation independently of proliferation in zebrafish

Authors
Lee, S.H., So, J., Shin, D.
ID
ZDB-PUB-230111-5
Date
2023
Source
Hepatology (Baltimore, Md.)   77(4): 1198-1210 (Journal)
Registered Authors
Shin, Donghun, So, Juhoon
Keywords
none
MeSH Terms
  • Animals
  • Cell Proliferation
  • Cell Transdifferentiation/physiology
  • Cholestasis*/metabolism
  • Epithelial Cells
  • Hepatocytes/metabolism
  • Liver
  • Liver Diseases*/metabolism
  • Liver Regeneration/physiology
  • Zebrafish
(all 10)
PubMed
36626626 Full text @ Hepatology
Abstract
Background aims Injury to biliary epithelial cells (BECs) lining the hepatic bile ducts leads to cholestatic liver diseases. Upon severe biliary damage, hepatocytes can convert to BECs, thereby contributing to liver recovery. Given a potential of augmenting this hepatocyte-to-BEC conversion as a therapeutic option for cholestatic liver diseases, it will be important to thoroughly understand the cellular and molecular mechanisms of the conversion process.
Approach results Towards this aim, we have established a zebrafish model for hepatocyte-to-BEC conversion by employing Tg(fabp10a:CFP-NTR) zebrafish with a temporal inhibition of Notch signaling during regeneration. Cre/loxP-mediated permanent and H2B-mCherry-mediated short-term lineage tracing revealed that in the model, all BECs originate from hepatocytes. During the conversion, BEC markers are sequentially induced in the order of Sox9b, Yap/Taz, Notch activity/epcam, and Alcama/krt18; the expression of the hepatocyte marker Bhmt disappears between the Sox9b and Yap/Taz induction. Importantly, live time-lapse imaging unambiguously revealed transdifferentiation of hepatocytes into BECs: hepatocytes convert to BECs without transitioning through a proliferative intermediate state. In addition, using compounds and transgenic and mutant lines that modulate Notch and Yap signaling, we found that both Notch and Yap signaling are required for the conversion even in Notch- and Yap-overactivating settings.
Conclusions Hepatocyte-to-BEC conversion occurs through transdifferentiation independently of proliferation, and Notch and Yap signaling control the process in parallel with a mutually positive interaction. The new zebrafish model will further contribute to a thorough understanding of the mechanisms of the conversion process.
Genes / Markers
Marker Marker Type Name
fabp10aGENEfatty acid binding protein 10a, liver basic
fbxw7GENEF-box and WD repeat domain containing 7
hist2h2lGENEhistone 2, H2, like
krt18a.1GENEkeratin 18a, tandem duplicate 1
mitfaGENEmelanocyte inducing transcription factor a
mpv17GENEmitochondrial inner membrane protein MPV17
notch3GENEnotch receptor 3
sox9bGENESRY-box transcription factor 9b
yap1GENEYes1 associated transcriptional regulator
zgc:114046GENEzgc:114046
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Figures
No images available
Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
a9
    		Complex
    bns19
      		Small Deletion
      co17TgTransgenic Insertion
        fh332
          		Point Mutation
          jh63TgTransgenic Insertion
            pt602TgTransgenic Insertion
              pt621TgTransgenic Insertion
                pt622TgTransgenic Insertion
                  pt623TgTransgenic Insertion
                    s931TgTransgenic Insertion
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                      Human Disease / Model
                      No data available
                      Sequence Targeting Reagents
                      No data available
                      Fish
                      No data available
                      Antibodies
                      Name Type Antigen Genes Isotypes Host Organism
                      Ab1-abcb11polyclonalRabbit
                      Ab1-wwtr1monoclonalIgGRabbit
                      Ab10-pcnapolyclonal
                        		Rabbit
                        zn-5monoclonalIgG1Mouse
                        1 - 4 of 4
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                        Orthology
                        Engineered Foreign Genes
                        Marker Marker Type Name
                        CFPEFGCFP
                        CreEFGCre
                        ECFPEFGECFP
                        EGFPEFGEGFP
                        GAL4FFEFGGAL4FF
                        mCherryEFGmCherry
                        NTREFGNTR
                        RFPEFGRFP
                        VenusEFGVenus
                        1 - 9 of 9
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                        Mapping
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                        Citation
                        Lee, S.H., So, J., Shin, D. (2023) Hepatocyte-to-cholangiocyte conversion occurs through transdifferentiation independently of proliferation in zebrafish. Hepatology (Baltimore, Md.). 77(4):1198-1210.