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
- PubMed
- 36626626 Full text @ Hepatology
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.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping