Notch Inhibition Promotes Differentiation of Liver Progenitor Cells into Hepatocytes via sox9b Repression in Zebrafish
Joint Authors
Russell, Jacquelyn O.
Ko, Sungjin
Monga, Satdarshan P.
Shin, Donghun
Source
Issue
Vol. 2019, Issue 2019 (31 Dec. 2019), pp.1-11, 11 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2019-03-12
Country of Publication
Egypt
No. of Pages
11
Abstract EN
Liver regeneration after most forms of injury is mediated through the proliferation of hepatocytes.
However, when hepatocyte proliferation is impaired, such as during chronic liver disease, liver progenitor cells (LPCs) arising from the biliary epithelial cell (BEC) compartment can give rise to hepatocytes to mediate hepatic repair.
Promotion of LPC-to-hepatocyte differentiation in patients with chronic liver disease could serve as a potentially new therapeutic option, but first requires the identification of the molecular mechanisms driving this process.
Notch signaling has been identified as an important signaling pathway promoting the BEC fate during development and has also been implicated in regulating LPC differentiation during regeneration.
SRY-related HMG box transcription factor 9 (Sox9) is a direct target of Notch signaling in the liver, and Sox9 has also been shown to promote the BEC fate during development.
We have recently shown in a zebrafish model of LPC-driven liver regeneration that inhibition of Hdac1 activity through MS-275 treatment enhances sox9b expression in LPCs and impairs LPC-to-hepatocyte differentiation.
Therefore, we hypothesized that inhibition of Notch signaling would promote LPC-to-hepatocyte differentiation by repressing sox9b expression in zebrafish.
We ablated the hepatocytes of Tg(fabp10a:CFP-NTR) larvae and blocked Notch activation during liver regeneration through treatment with γ-secretase inhibitor LY411575 and demonstrated enhanced induction of Hnf4a in LPCs.
Alternatively, enhancing Notch signaling via Notch3 intracellular domain (N3ICD) overexpression impaired Hnf4a induction.
Hepatocyte ablation in sox9b heterozygous mutant embryos enhanced Hnf4a induction, while BEC-specific Sox9b overexpression impaired LPC-to-hepatocyte differentiation.
Our results establish the Notch-Sox9b signaling axis as inhibitory to LPC-to-hepatocyte differentiation in a well-established in vivo LPC-driven liver regeneration model.
American Psychological Association (APA)
Russell, Jacquelyn O.& Ko, Sungjin& Monga, Satdarshan P.& Shin, Donghun. 2019. Notch Inhibition Promotes Differentiation of Liver Progenitor Cells into Hepatocytes via sox9b Repression in Zebrafish. Stem Cells International،Vol. 2019, no. 2019, pp.1-11.
https://search.emarefa.net/detail/BIM-1209739
Modern Language Association (MLA)
Russell, Jacquelyn O.…[et al.]. Notch Inhibition Promotes Differentiation of Liver Progenitor Cells into Hepatocytes via sox9b Repression in Zebrafish. Stem Cells International No. 2019 (2019), pp.1-11.
https://search.emarefa.net/detail/BIM-1209739
American Medical Association (AMA)
Russell, Jacquelyn O.& Ko, Sungjin& Monga, Satdarshan P.& Shin, Donghun. Notch Inhibition Promotes Differentiation of Liver Progenitor Cells into Hepatocytes via sox9b Repression in Zebrafish. Stem Cells International. 2019. Vol. 2019, no. 2019, pp.1-11.
https://search.emarefa.net/detail/BIM-1209739
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-1209739