PMID- 25915586
OWN - NLM
STAT- MEDLINE
DCOM- 20150812
LR  - 20220409
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 125
IP  - 6
DP  - 2015 Jun
TI  - Lineage fate of ductular reactions in liver injury and carcinogenesis.
PG  - 2445-57
LID - 78585 [pii]
LID - 10.1172/JCI78585 [doi]
AB  - Ductular reactions (DRs) are observed in virtually all forms of human liver 
      disease; however, the histogenesis and function of DRs in liver injury are not 
      entirely understood. It is widely believed that DRs contain bipotential liver 
      progenitor cells (LPCs) that serve as an emergency cell pool to regenerate both 
      cholangiocytes and hepatocytes and may eventually give rise to hepatocellular 
      carcinoma (HCC). Here, we used a murine model that allows highly efficient and 
      specific lineage labeling of the biliary compartment to analyze the histogenesis 
      of DRs and their potential contribution to liver regeneration and carcinogenesis. 
      In multiple experimental and genetic liver injury models, biliary cells were the 
      predominant precursors of DRs but lacked substantial capacity to produce new 
      hepatocytes, even when liver injuries were prolonged up to 12 months. Genetic 
      modulation of NOTCH and/or WNT/beta-catenin signaling within lineage-tagged DRs 
      impaired DR expansion but failed to redirect DRs from biliary differentiation 
      toward the hepatocyte lineage. Further, lineage-labeled DRs did not produce 
      tumors in genetic and chemical HCC mouse models. In summary, we found no evidence 
      in our system to support mouse biliary-derived DRs as an LPC pool to replenish 
      hepatocytes in a quantitatively relevant way in injury or evidence that DRs give 
      rise to HCCs.
FAU - Jors, Simone
AU  - Jors S
FAU - Jeliazkova, Petia
AU  - Jeliazkova P
FAU - Ringelhan, Marc
AU  - Ringelhan M
FAU - Thalhammer, Julian
AU  - Thalhammer J
FAU - Durl, Stephanie
AU  - Durl S
FAU - Ferrer, Jorge
AU  - Ferrer J
FAU - Sander, Maike
AU  - Sander M
FAU - Heikenwalder, Mathias
AU  - Heikenwalder M
FAU - Schmid, Roland M
AU  - Schmid RM
FAU - Siveke, Jens T
AU  - Siveke JT
FAU - Geisler, Fabian
AU  - Geisler F
LA  - eng
GR  - 101033/Wellcome Trust/United Kingdom
GR  - R01 DK078803/DK/NIDDK NIH HHS/United States
GR  - DK078803/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150427
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
SB  - IM
MH  - Animals
MH  - Bile Ducts/*metabolism/pathology
MH  - Carcinoma, Hepatocellular/chemically induced/genetics/*metabolism/pathology
MH  - Hepatocytes/metabolism/pathology
MH  - Humans
MH  - Liver/*injuries/*metabolism/pathology
MH  - Liver Neoplasms, Experimental/chemically induced/genetics/*metabolism/pathology
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Stem Cells/metabolism/pathology
MH  - Wnt Signaling Pathway/drug effects/genetics
PMC - PMC4497753
EDAT- 2015/04/29 06:00
MHDA- 2015/08/13 06:00
PMCR- 2015/09/01
CRDT- 2015/04/28 06:00
PHST- 2014/08/17 00:00 [received]
PHST- 2015/03/20 00:00 [accepted]
PHST- 2015/04/28 06:00 [entrez]
PHST- 2015/04/29 06:00 [pubmed]
PHST- 2015/08/13 06:00 [medline]
PHST- 2015/09/01 00:00 [pmc-release]
AID - 78585 [pii]
AID - 10.1172/JCI78585 [doi]
PST - ppublish
SO  - J Clin Invest. 2015 Jun;125(6):2445-57. doi: 10.1172/JCI78585. Epub 2015 Apr 27.