Contribution of Mature Hepatocytes to Biliary Regeneration in Rats with Acute and Chronic Biliary Injury.
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...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4550468?pdf=render |
| _version_ | 1818982521943097344 |
|---|---|
| author | Ya-Hui Chen Hui-Ling Chen Chin-Sung Chien Shang-Hsin Wu Yi-Tian Ho Chun-Hsien Yu Mei-Hwei Chang |
| author_facet | Ya-Hui Chen Hui-Ling Chen Chin-Sung Chien Shang-Hsin Wu Yi-Tian Ho Chun-Hsien Yu Mei-Hwei Chang |
| author_sort | Ya-Hui Chen |
| collection | DOAJ |
| description | 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-1β (HNF-1β) 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. |
| first_indexed | 2024-12-20T17:48:33Z |
| format | Article |
| id | doaj.art-9c513eaeb94548e19f5e7b85c3e1bc1e |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T17:48:33Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-9c513eaeb94548e19f5e7b85c3e1bc1e2022-12-21T19:30:54ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01108e013432710.1371/journal.pone.0134327Contribution of Mature Hepatocytes to Biliary Regeneration in Rats with Acute and Chronic Biliary Injury.Ya-Hui ChenHui-Ling ChenChin-Sung ChienShang-Hsin WuYi-Tian HoChun-Hsien YuMei-Hwei ChangWhether 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-1β (HNF-1β) 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.http://europepmc.org/articles/PMC4550468?pdf=render |
| spellingShingle | Ya-Hui Chen Hui-Ling Chen Chin-Sung Chien Shang-Hsin Wu Yi-Tian Ho Chun-Hsien Yu Mei-Hwei Chang Contribution of Mature Hepatocytes to Biliary Regeneration in Rats with Acute and Chronic Biliary Injury. PLoS ONE |
| title | Contribution of Mature Hepatocytes to Biliary Regeneration in Rats with Acute and Chronic Biliary Injury. |
| title_full | Contribution of Mature Hepatocytes to Biliary Regeneration in Rats with Acute and Chronic Biliary Injury. |
| title_fullStr | Contribution of Mature Hepatocytes to Biliary Regeneration in Rats with Acute and Chronic Biliary Injury. |
| title_full_unstemmed | Contribution of Mature Hepatocytes to Biliary Regeneration in Rats with Acute and Chronic Biliary Injury. |
| title_short | Contribution of Mature Hepatocytes to Biliary Regeneration in Rats with Acute and Chronic Biliary Injury. |
| title_sort | contribution of mature hepatocytes to biliary regeneration in rats with acute and chronic biliary injury |
| url | http://europepmc.org/articles/PMC4550468?pdf=render |
| work_keys_str_mv | AT yahuichen contributionofmaturehepatocytestobiliaryregenerationinratswithacuteandchronicbiliaryinjury AT huilingchen contributionofmaturehepatocytestobiliaryregenerationinratswithacuteandchronicbiliaryinjury AT chinsungchien contributionofmaturehepatocytestobiliaryregenerationinratswithacuteandchronicbiliaryinjury AT shanghsinwu contributionofmaturehepatocytestobiliaryregenerationinratswithacuteandchronicbiliaryinjury AT yitianho contributionofmaturehepatocytestobiliaryregenerationinratswithacuteandchronicbiliaryinjury AT chunhsienyu contributionofmaturehepatocytestobiliaryregenerationinratswithacuteandchronicbiliaryinjury AT meihweichang contributionofmaturehepatocytestobiliaryregenerationinratswithacuteandchronicbiliaryinjury |