Zonal expression of hepatocytic marker enzymes during liver repopulation

Abstract

Hepatocytes are metabolically specialised cells displaying distinctive gene expression patterns within the liver lobule. Here, we investigate whether pre-cultured adult rat hepatocytes adopt periportal and pericentral enzyme expression following their transplantation into the regenerating rat liver. Isolated primary rat hepatocytes, representing a mixture of both periportal and pericentral origin, lost expression of carbamoyl phosphate synthetase I (CPS I) and cytochrome P450 subtype 2B1 (CYP2B1) in culture as shown by immunofluorescence and Western blot analysis. Accordingly, urea synthesis and CYP2B1 enzyme activity decreased. Hepatocytes from DPPIV (CD26) wild type rats were cultured for 4 and 7 days, and then transplanted into the livers of CD26 deficient rats following prior treatment with retrorsine and partial hepatectomy to drive selective donor cell proliferation. CD26 positive donor cells engrafted in the periportal regions and grew in clusters expanding into the parenchyma as time proceeded. Ten weeks after transplantation, cells derived from donors surrounding the portal veins expressed CPS I, but not CYP2B1. The reverse was true for CD26 positive cells in close proximity to the central veins displaying immunoreactivity to CYP2B1, but no longer to CPS I. Hepatocytes lose their specific marker enzyme expression in culture. After transplantation, donor hepatocytes proliferate in the host parenchyma whilst acquiring the position-specific enzyme expression of the surrounding periportal and pericentral host hepatocytes. These results indicate the high degree of plasticity of gene expression in hepatocytes subjected to a change in microenvironment.

Striking LD50 variation associated with fluctuations of CYP2E1-positive cells in hepatic lobule during chronic CCl4 exposure in mice

“…It has been reported that donor hepatocytes acquired positionspecific enzyme expression while proliferating in the liver parenchyma of a recipient rat with prior treatment of retrosine and partial hepatectomy. This finding indicates that hepatocytes are subject to microenvironmental change in their plasticity of gene expression [36]. Taken together, it is highly likely that CCl 4 damages the microenvironment of zone 3.…”

Phenotype and growth behavior of residual β-catenin-positive hepatocytes in livers of β-catenin-deficient mice

“…In contrast, it was demonstrated that periportal hepatocytes are capable of expressing perivenous marker proteins in cell culture (Schrode et al 1990). Accordingly, hepatocytes lose their aboriginal expression profiles in culture and acquire a position-specific marker enzyme pattern after re-transplantation and engraftment into the liver (Gupta et al 1999;Koenig et al 2007). Furthermore, during liver regeneration after destruction of perivenous hepatocytes by CCl 4 , periportal-derived hepatocytes assume the position of the destructed cells and adopt a perivenous phenotype (Schols et al 1990).…”

Evaluation of porcine mesenchymal stem cells for therapeutic use in human liver cancer

“…In line with this assumption, Runge et al found that primary hepatocytes lose their functional abilities in serum-free long-term culture (38). This seems to be a consequence of molecular downregulation rather than cellular de-differentiation, as all functional abilities are restored once the cells are transplanted into a recipient liver (40,41). Differentiated MSC are suggested to lose their functional abilities also in extended cultures, and Stock et al recommend that hepatocyte-like human MSC should not be grown for more than 21 days (2).…”