Loss of reciprocal modulations of growth and liver function of hepatoma cells in culture by contact with cells or cell membranes.

Abstract

In mature rat hepatocytes in primary culture, many metabolic functions and cell growth are controlled reciprocally by cell density, and this reciprocal regulation is mediated by a cell-surface modulator through cell-cell contact. Cultured RY-121B cells from Reuber hepatoma and MH1Cj cells from Morris hepatoma, which retain some liverspecific functions, did not show any cell-density dependency of either cell growth or hepatocyte-specific functions, such as induction of tyrosine aminotransferase by dexamethasone. However, when RY-121B cells were cocultured with a low density of rat hepatocytes as monolayers in direct contact, they exerted contact-dependent control of DNA synthesis and of differentiated function of the hepatocytes. Furthermore, plasma membranes from various tumor cells including these hepatoma cells had strong modulator activity on primary cultures of normal rat hepatocytes, and their activity mimicked the reciprocal effects of cell density on DNA synthesis and induction of tyrosine aminotransferase. On the contrary, addition of plasma membranes from normal adult rat liver to sparse cultures of RY-121B or MH1Cj cells did not cause any inhibition of active DNA synthesis or enhancement of induction of tyrosine aminotransferase in these cells. These results suggest that hepatoma cells have lost cell density-dependent regulations of many cellular activities and cell growth because they have lost the ability to respond to the cell surface modulator, although they retain modulator activity on their plasma membranes.

Regulation of bile canalicular network formation and maintenance by AMP-activated protein kinase and LKB1

“…After overnight growth, hepatocytes were overlaid with collagen and cultured in a humidified 37°C incubator in 5% CO 2 (Chandra et al, 2001). Cell density was 2.56ϫ10 5 /cm 2 , which is similar to in vivo density (2-3ϫ10 5 /cm 2 ) (Nakamura et al, 1984).…”

Hepatitis C virus cell-cell transmission in hepatoma cells in the presence of neutralizing antibodies

“…The principal site of HCV replication in vivo is thought to be hepatocytes within the liver, which form polarized sheets where the cells are at high density (2-3.0 ϫ 10 5 hepatocytes/cm 2 of liver tissue). 21 In contrast, HCV RNA has been reported to replicate more efficiently in actively proliferating cells, demonstrating reduced replication in cells at high density. 22,23 Because the majority of hepatocytes within the liver are not proliferating and are arrested in G 0 , these data suggest a delicate balance between the cell requirements that are optimal for HCV entry and transmission versus those required for efficient viral RNA replication.…”

Cell-Cell Contact-Mediated Hepatitis C Virus (HCV) Transfer, Productive Infection, and Replication and Their Requirement for HCV Receptors

“…The liver is one of the organs with an extremely high cell density (2 ϫ 10 5 to 3.0 ϫ 10 5 hepatocytes/cm 2 [56]), which provides HCV with numerous cell-cell contact sites. In chronically HCV-infected liver, viral replication and the intrahepatic HCV RNA level are very low (7 to 64 genomic equivalents per cell) (57,58), and nAbs and other immunological responses are often present (59).…”