Proliferation of hepatic lineage cells of normal C57BL and interleukin-6 knockout mice after cocaine-induced periportal injury

Abstract

The cellular response to periportal liver injury, induced by phenobarbital feeding and cocaine injection, is used to compare the restitutive proliferation of hepatocytes, cholangiocytes, and oval cells in the livers of normal control to those of interleukin-6 (IL-6) knockout mice. After this injury hepatocytes in noninjured middle and central zones start to proliferate first, followed by proliferation of cholangiocytes and intraportal oval cells. Proliferation of all cell types peaks at 2 days, but oval cells continue to proliferate and differentiate through days 4 and 6 as they reconstitute the necrotic zone. By day 10, the injured zone is completely repaired, and no dividing cells remain. During the first 3 to 4 days after injury, the number of proliferating hepatocytes, cholangiocytes, and sinusoidal cells is lower in IL-6 knockout mice than in normal mice, whereas the number of dividing oval cells is higher. However, overall repair of the injury is accomplished in the same time period in both groups. During repair of the periportal zone, oval cells acquire differentiation markers of hepatocytes as they cross the zone of injury. In conclusion, the phenobarbital/cocaine injury model is useful to study restitutive proliferation of mouse liver cell lineages. The proliferative response in IL-6 knockout mice shows that IL-6 is not required for proliferation of liver cells; timely repair of liver injury occurs in both normal and IL-6 knockout mice. Increased proliferation of oval cells in IL-6 knockout mice may compensate for the lower proliferation of other liver cell types. (HEPATOLOGY 2000;31:948-955.)

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

“…41 Yet, comparison of the cellular response to cocaineinduced periportal injury in normal and IL-6 -/-mice demonstrated increased proliferation of periportal oval cells in IL-6 -/-mice to compensate for the decrease in restorative proliferation of hepatocytes, biliary epithelia and sinusoidal cells. 44 Ten days after injury, the liver was completely repaired in all mice, indicating that IL-6 is not essential for oval cell proliferation. It is feasible that other members of the IL-6 family, including leukemia inhibitory factor (LIF) and/or oncostatin M (OSM), may compensate for the absence of IL-6 in these mice.…”

Activation of NF-κB and STAT3 in rat oval cells during 2-acetylaminofluorene/partial hepatectomy-induced liver regeneration

“…The importance of IL-6 in oval cell-mediated regeneration is less clear because an increased proliferation of oval cells was found in IL-6 knockout mice after cocaine-induced periportal injury. 17 Together, these observations suggest that growth regulation of hepatocytes and liver stem cells may share a number of common features, but distinct features for each of these cell lineages also may exist.…”

Immunohistochemical study of hepatic oval cells in human chronic viral hepatitis

“…Liver regeneration is usually achieved by the entry of normally proliferatively quiescent, differentiated hepatocytes into the cell cycle, but, when hepatocyte regeneration is defective, oval cells can migrate outward from the portal tracts and then differentiate into hepatocytes [1][2][3] . The term oval cells described as small cells with oval nuclei that arise in the periphery of the portal tracts in rat models of hepatocarcin ogenesis and injury [4][5][6][7] . These cells are thought to have both clonogenic and bipotential capacity, i.e., the ability to proliferate and differentiate into cells of either hepatocyte or biliary epithelial cells [8] .…”