Plasticity of Hepatocytes in liver regeneration
Date Issued
2014
Date
2014
Author(s)
Chen, Ya-Hui
Abstract
Hepatocytes are cells with high plasticity. Mature hepatocyte proliferation is usually responsible for liver regeneration after most causes of injury. However, under the special contribution of liver damage, mature hepatocytes can function as facultative stem cells for each other and replenish the inhibited cellular compartment by a process of trans-differentiation, involving complex signaling pathways. Mechanism of its regulation is still unclear.
The potential lineage relationship between hepatic oval cells, small hepatocyte-like progenitor cells (SHPCs), and hepatocytes in liver regeneration is debated. SHPCs are a type of progenitor cells group and express phenotypic characteristics of fetal hepatoblasts, hepatic oval cells, and mature hepatocytes. To test whether mature hepatocytes can give rise to SHPCs, rats with dipeptidyl peptidase IV (DPPIV) chimeric livers, which harbored endogenous DPPIV-deficient hepatocytes and transplanted DPPIV-positive hepatocytes, were subjected to retrorsine treatment followed by partial hepatectomy (PH). DPPIV-positive hepatocytes comprised about half of the DPPIV chimeric liver mass. Tissues from DPPIV chimeric livers after retrorsine/PH treatment showed large numbers of SHPC clusters. None of the SHPC clusters were stained positive for DPPIV in any analyzed samples. Furthermore, serial sections stained for gamma-glutamyl-transpeptidase (GGT, a marker of fetal hepatoblasts) and glucose-6-phosphatase (G6Pase, a marker of mature hepatocytes) showed SHPCs are a heterogeneous population of cells at different stages of differentiation in hepatic progenitor cell and hepatocyte lineage. Using double immunofluorescence staining for markers specific for hepatic oval cells (CK-19/OV-6, Laminin, EpCAM) and hepatocytes (HNF-4α, C/EBPα) in serial sections, we find that a lineage relationship was present within a single oval cell proliferation and between oval cell proliferations and SHPC clusters. Extensive elimination of oval cell response by repeated administration of 4,4’-methylenedianiline (DAPM) to retrorsine-exposed rats impaired the emergence of SHPC clusters. DPPIV-positive hepatic oval cells are transplanted into the DPPIV-deficient rat subjected to retrorsine treatment and followed by partial hepatectomy. The DPPIV-positive SHPC clusters is observed. These findings highly suggest the hepatic oval cells but not mature hepatocytes as the origin of SHPC clusters in retrorsine-exposed rats.
However, we have recently used in vivo lineage tracing technique in rats and resolved the debate on the lineage relationship between mature SHPCs in retrorsine-exposed rats after PH. We have demonstrated that mature hepatocytes do not give rise to SHPCs. Taken together, these studies prompted us to hypothesize that being a terminal differentiated cell type, mature hepatocytes can not convert into BECs in the damaged livers. Therefore, whether hepatocytes can convert into biliary epithelial cells (BECs) during liver injury is much debated. To test this concept, we traced the fate of genetically labeled (DPPIV-positive) hepatocytes in hepatocyte transplantation model following acute hepato-biliary injury induced by 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 DPPIV-deficient hepatocytes are restricted to proliferate by retrorsine. We found that mature hepatocytes underwent a stepwise conversion into BECs. 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 identity, proceeded through an intermediate state, acquired a biliary phenotype, and subsequently formed bile ducts along the hilum-to-periphery axis. Additionally, in DPPIV-chimeric liver model, periportally located hepatocytes expressing 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. These findings highly suggest that mature hepatocytes contribute to the biliary regeneration in the environment of acute and chronic biliary injury through a mechanism similar to fetal development of biliary duct without the need of exogenously genetic or epigenetic manipulation. The Notch signaling pawthay may regulate this response.
Finally, these results showed hepatocytes have a strong ability for regeneration during liver damage in various environment. Hepatocytes can self-replicate proliferation or transdifferentiation to repair the liver.
Subjects
肝細胞
肝細胞移植
卵圓幹細胞
小肝細胞樣祖細胞
肝臟再生
細胞分化
轉分化
Type
thesis
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