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2015 ; 10
(8
): e0134327
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Contribution of Mature Hepatocytes to Biliary Regeneration in Rats with Acute and
Chronic Biliary Injury
#MMPMID26308208
Chen YH
; Chen HL
; Chien CS
; Wu SH
; Ho YT
; Yu CH
; Chang MH
PLoS One
2015[]; 10
(8
): e0134327
PMID26308208
show ga
Whether hepatocytes can convert into biliary epithelial cells (BECs) during
biliary injury is much debated. To test this concept, we traced the fate of
genetically labeled [dipeptidyl peptidase IV (DPPIV)-positive] hepatocytes in
hepatocyte transplantation model following acute hepato-biliary injury induced by
4,4'-methylene-dianiline (DAPM) and D-galactosamine (DAPM+D-gal) and in
DPPIV-chimeric liver model subjected to acute (DAPM+D-gal) or chronic biliary
injury caused by DAPM and bile duct ligation (DAPM+BDL). In both models before
biliary injury, BECs are uniformly DPPIV-deficient and proliferation of
DPPIV-deficient hepatocytes is restricted by retrorsine. We found that mature
hepatocytes underwent a stepwise conversion into BECs after biliary injury. In
the hepatocyte transplantation model, DPPIV-positive hepatocytes entrapped
periportally proliferated, and formed two-layered plates along portal veins.
Within the two-layered plates, the hepatocytes gradually lost their hepatocytic
identity, proceeded through an intermediate state, acquired a biliary phenotype,
and subsequently formed bile ducts along the hilum-to-periphery axis. In
DPPIV-chimeric liver model, periportal hepatocytes expressing hepatocyte nuclear
factor-1? (HNF-1?) were exclusively DPPIV-positive and were in continuity to
DPPIV-positives bile ducts. Inhibition of hepatocyte proliferation by additional
doses of retrorsine in DPPIV-chimeric livers prevented the appearance of
DPPIV-positive BECs after biliary injury. Moreover, enriched DPPIV-positive
BEC/hepatic oval cell transplantation produced DPPIV-positive BECs or bile ducts
in unexpectedly low frequency and in mid-lobular regions. These results together
suggest that mature hepatocytes but not contaminating BECs/hepatic oval cells are
the sources of periportal DPPIV-positive BECs. We conclude that mature
hepatocytes contribute to biliary regeneration in the environment of acute and
chronic biliary injury through a ductal plate configuration without the need of
exogenously genetic or epigenetic manipulation.