Differentiation of oval cells into duct-like cells in preneoplastic liver of rats placed on a choline-deficient diet supplemented with ethionine

Abstract

Feeding male Wistar rats a choline-deficient diet containing 0.07% DL-ethionine (CDE diet) for up to 5 weeks results in the production of two distinct non-parenchymal cell populations, oval and duct-like cells. These cells can undergo replication and display different patterns of expression of glutathione S-transferases (GSTs) and pyruvate kinases (PKs). Oval cells were first detected around the periportal region after 1 week of CDE treatment and infiltrated the parenchyma after 2 weeks. Duct-like structures first appeared as isolated ducts in the parenchymal region at 2 weeks and were easily detected after 2.5 weeks. These duct-like structures differed from the bile ducts which reside in the portal region. Large concentrations of duct-like structures in cyst-like clusters were detected after 5 weeks. Enlargement of these structures from single ducts to clusters of up to 20 ducts was observed over 3-5 weeks of CDE treatment. The number of cells forming a duct increased from 5 to 30 cells. We established a double immunocytochemical staining technique to characterize the oval and duct-like cells for their expression of GSTs and PKs. pi GST and M2-PK, which are fetal hepatocytes isoenzymes, are present in virtually all the oval and duct-like cells. Most of the oval cells are devoid of the adult hepatocytes markers, alpha GST, mu GST and L-PK. There are two sub-populations of duct-like cells, one which expresses only fetal markers and the other which co-expresses the adult and fetal isoenzymes. Hence, oval cells display characteristics of fetal hepatocytes and some duct-like cells appear more mature than oval cells. Using a combination of double immunocytochemical and [3H]thymidine labelling techniques we have established that oval cells differentiate into duct-like cells.

Differential lymphotoxin-? and interferon gamma signaling during mouse liver regeneration induced by chronic and acute injury

“…[32][33][34] Interestingly, the loss of IFN␥ signaling leads to a reduction in MPK ϩ oval cells, but not A6 ϩ oval cells. In our hands, A6 staining is confined to bile ducts in normal liver and mainly ductal and periductal oval cells in CDE-treated liver.…”

Oval Cell Numbers in Human Chronic Liver Diseases Are Directly Related to Disease Severity

“…13,20 When oval cells are isolated from animals placed on a choline-deficient, ethionine-supplemented diet, they rapidly deteriorate in culture, suggesting that exogenous factors are required for their survival and proliferation. 13 In the current human study, oval cells were often found in close association with fibrous tissue in the liver, often proliferating along the tracts from the expanded portal regions and along the limiting plates surrounding regenerative nodules. In addition, oval cells were often observed in close association with inflammatory cells, particularly in patients with hepatitis C. These observations suggest that cytokines or other factors produced by inflammatory Figure 1.…”

“…[13][14][15]20,21 The marker M2-PK has been found to be the most reliable marker for oval cells in our laboratory because it does not stain ductal cells as -GST does and it is not expressed in some adult hepatocytes in the same manner as ␣-fetoprotein. [13][14][15] M2-PK is detected in oval cells of adult liver. 15 We have observed that infiltrating lymphocytes in chronic hepatitis C infection can also exhibit some staining for M2-PK.…”

“…One of the earliest cellular changes observed is the proliferation of oval cells in the periportal region of the liver, followed by infiltration of these cells into the liver lobule. 12,13 Oval cell proliferation has also been reported in rodents following chronic exposure to ethanol or iron. 15,16 In humans, oval cells have been reported in hepatitis B-associated HCC and chronic liver disease associated with ductular proliferation.…”

Oval cell‐mediated liver regeneration: Role of cytokines and growth factors

“…This is in agreement with our observation that oval cells differentiate into bile duct cells in vivo , as shown by GST and PK immunohistochemistry. 16 …”