PMID- 28599080
OWN - NLM
STAT- MEDLINE
DCOM- 20171101
LR  - 20190412
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 66
IP  - 5
DP  - 2017 Nov
TI  - Bone morphogenetic protein signaling governs biliary-driven liver regeneration in 
      zebrafish through tbx2b and id2a.
PG  - 1616-1630
LID - 10.1002/hep.29309 [doi]
AB  - Upon mild liver injury, new hepatocytes originate from preexisting hepatocytes. 
      However, if hepatocyte proliferation is impaired, a manifestation of severe liver 
      injury, biliary epithelial cells (BECs) contribute to new hepatocytes through BEC 
      dedifferentiation into liver progenitor cells (LPCs), also termed oval cells or 
      hepatoblast-like cells (HB-LCs), and subsequent differentiation into hepatocytes. 
      Despite the identification of several factors regulating BEC dedifferentiation 
      and activation, little is known about factors involved in the regulation of LPC 
      differentiation into hepatocytes during liver regeneration. Using a zebrafish 
      model of near-complete hepatocyte ablation, we show that bone morphogenetic 
      protein (Bmp) signaling is required for BEC conversion to hepatocytes, 
      particularly for LPC differentiation into hepatocytes. We found that severe liver 
      injury led to the up-regulation of genes involved in Bmp signaling, including 
      smad5, tbx2b, and id2a, in the liver. Bmp suppression did not block BEC 
      dedifferentiation into HB-LCs; however, the differentiation of HB-LCs into 
      hepatocytes was impaired due to the maintenance of HB-LCs in an undifferentiated 
      state. Later Bmp suppression did not affect HB-LC differentiation but increased 
      BEC number through proliferation. Notably, smad5, tbx2b, and id2a mutants 
      exhibited similar liver regeneration defects as those observed in Bmp-suppressed 
      livers. Moreover, BMP2 addition promoted the differentiation of a murine LPC line 
      into hepatocytes in vitro. CONCLUSIONS: Bmp signaling regulates BEC-driven liver 
      regeneration through smad5, tbx2b, and id2a: it regulates HB-LC differentiation 
      into hepatocytes through tbx2b and BEC proliferation through id2a; our findings 
      provide insights into promoting innate liver regeneration as a novel therapy. 
      (Hepatology 2017;66:1616-1630).
CI  - (c) 2017 by the American Association for the Study of Liver Diseases.
FAU - Choi, Tae-Young
AU  - Choi TY
AD  - Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan 
      Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA.
FAU - Khaliq, Mehwish
AU  - Khaliq M
AD  - Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan 
      Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA.
FAU - Tsurusaki, Shinya
AU  - Tsurusaki S
AD  - Department of Regenerative Medicine, Research Institute, National Center for 
      Global Health and Medicine, Tokyo, Japan.
FAU - Ninov, Nikolay
AU  - Ninov N
AD  - Department of Biochemistry and Biophysics, Programs in Developmental and Stem 
      Cell Biology, Genetics and Human Genetics, Diabetes Center, and Liver Center, 
      University of California, San Francisco, San Francisco, CA.
AD  - Department of Developmental Genetics, Max Planck Institute for Heart and Lung 
      Research, Bad Nauheim, Germany.
FAU - Stainier, Didier Y R
AU  - Stainier DYR
AD  - Department of Biochemistry and Biophysics, Programs in Developmental and Stem 
      Cell Biology, Genetics and Human Genetics, Diabetes Center, and Liver Center, 
      University of California, San Francisco, San Francisco, CA.
AD  - Department of Developmental Genetics, Max Planck Institute for Heart and Lung 
      Research, Bad Nauheim, Germany.
FAU - Tanaka, Minoru
AU  - Tanaka M
AD  - Department of Regenerative Medicine, Research Institute, National Center for 
      Global Health and Medicine, Tokyo, Japan.
FAU - Shin, Donghun
AU  - Shin D
AD  - Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan 
      Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA.
LA  - eng
GR  - F31 DK105714/DK/NIDDK NIH HHS/United States
GR  - R01 DK060322/DK/NIDDK NIH HHS/United States
GR  - R01 DK101426/DK/NIDDK NIH HHS/United States
GR  - R01 GM088040/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20170929
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Bone Morphogenetic Proteins)
RN  - 0 (Id2a protein, zebrafish)
RN  - 0 (Inhibitor of Differentiation Protein 2)
RN  - 0 (T-Box Domain Proteins)
RN  - 0 (Zebrafish Proteins)
RN  - 0 (tbx2b protein, zebrafish)
SB  - IM
MH  - Animals
MH  - Bone Morphogenetic Proteins/*metabolism
MH  - *Cell Differentiation
MH  - Cell Proliferation
MH  - Hepatocytes/cytology
MH  - Inhibitor of Differentiation Protein 2/*metabolism
MH  - *Liver Regeneration
MH  - T-Box Domain Proteins/*metabolism
MH  - Zebrafish
MH  - Zebrafish Proteins/*metabolism
PMC - PMC5650528
MID - NIHMS883515
EDAT- 2017/06/10 06:00
MHDA- 2017/11/02 06:00
PMCR- 2018/11/01
CRDT- 2017/06/10 06:00
PHST- 2017/01/18 00:00 [received]
PHST- 2017/05/04 00:00 [revised]
PHST- 2017/06/06 00:00 [accepted]
PHST- 2017/06/10 06:00 [pubmed]
PHST- 2017/11/02 06:00 [medline]
PHST- 2017/06/10 06:00 [entrez]
PHST- 2018/11/01 00:00 [pmc-release]
AID - 10.1002/hep.29309 [doi]
PST - ppublish
SO  - Hepatology. 2017 Nov;66(5):1616-1630. doi: 10.1002/hep.29309. Epub 2017 Sep 29.