Abstract
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.
Highlights
The liver has an enormous capacity to regenerate after injury [1,2,3]
While some studies have shown that hepatocytes undergo widespread hepatocyte-to-biliary epithelial cells (BECs) reprogramming following bile duct ligation (BDL) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet induced injury [13,17,18], the others have found no evidence that chronic biliary injury caused by BDL or DDC diet induces conversion of hepatocytes into BECs [11,16]
We chose to perform hepatocyte transplantation at day 1 after R+DAPM+D-gal when the rats were in maximal hepatobiliary injury or day 4 when the bile ducts appeared to repair from injury
Summary
The liver has an enormous capacity to regenerate after injury [1,2,3]. In most situations, liver regeneration is mediated by self duplication of mature hepatocytes and biliary epithelial cells (BECs). Several major assays have been used to document the transdifferentiation potential of hepatocytes: in vitro clonogenic growth, cell transplantation, forced activation of Notch signaling, and in vivo lineage tracing [10,11,12,13,14,15,16,17,18,19]. Forced activation of Notch signaling can reprogram hepatocytes into BECs in mice [17,19] These studies provide persuasive data, recent in vivo hepatocyte fate tracing studies using genetic lineage tagging or rodents with chimeric livers in chronic biliary liver diseases reach different conclusions [11,13,16,17,18]. While some studies have shown that hepatocytes undergo widespread hepatocyte-to-BEC reprogramming following bile duct ligation (BDL) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet induced injury [13,17,18], the others have found no evidence that chronic biliary injury caused by BDL or DDC diet induces conversion of hepatocytes into BECs [11,16]
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