PMID- 30992706
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200929
IS  - 1687-966X (Print)
IS  - 1687-9678 (Electronic)
VI  - 2019
DP  - 2019
TI  - Notch Inhibition Promotes Differentiation of Liver Progenitor Cells into 
      Hepatocytes via sox9b Repression in Zebrafish.
PG  - 8451282
LID - 10.1155/2019/8451282 [doi]
LID - 8451282
AB  - 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 gamma-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.
FAU - Russell, Jacquelyn O
AU  - Russell JO
AUID- ORCID: 0000-0001-9928-2869
AD  - Department of Pathology, University of Pittsburgh, Pittsburgh, USA.
FAU - Ko, Sungjin
AU  - Ko S
AUID- ORCID: 0000-0002-6079-5939
AD  - Department of Pathology, University of Pittsburgh, Pittsburgh, USA.
AD  - Department of Developmental Biology, University of Pittsburgh, Pittsburgh, USA.
FAU - Monga, Satdarshan P
AU  - Monga SP
AD  - Department of Pathology, University of Pittsburgh, Pittsburgh, USA.
AD  - Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, USA.
AD  - Department of Medicine, University of Pittsburgh, Pittsburgh, USA.
AD  - McGowan Institute for Regenerative Medicine, University of Pittsburgh, 
      Pittsburgh, USA.
FAU - Shin, Donghun
AU  - Shin D
AUID- ORCID: 0000-0002-7975-9014
AD  - Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, USA.
AD  - Department of Developmental Biology, University of Pittsburgh, Pittsburgh, USA.
AD  - McGowan Institute for Regenerative Medicine, University of Pittsburgh, 
      Pittsburgh, USA.
LA  - eng
GR  - R01 DK101426/DK/NIDDK NIH HHS/United States
GR  - R01 DK062277/DK/NIDDK NIH HHS/United States
GR  - R01 CA204586/CA/NCI NIH HHS/United States
GR  - F31 DK115017/DK/NIDDK NIH HHS/United States
GR  - R01 DK100287/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20190312
PL  - United States
TA  - Stem Cells Int
JT  - Stem cells international
JID - 101535822
PMC - PMC6434270
EDAT- 2019/04/18 06:00
MHDA- 2019/04/18 06:01
PMCR- 2019/03/12
CRDT- 2019/04/18 06:00
PHST- 2018/10/25 00:00 [received]
PHST- 2019/01/12 00:00 [accepted]
PHST- 2019/04/18 06:00 [entrez]
PHST- 2019/04/18 06:00 [pubmed]
PHST- 2019/04/18 06:01 [medline]
PHST- 2019/03/12 00:00 [pmc-release]
AID - 10.1155/2019/8451282 [doi]
PST - epublish
SO  - Stem Cells Int. 2019 Mar 12;2019:8451282. doi: 10.1155/2019/8451282. eCollection 
      2019.