Depletion of activated hepatic stellate cell correlates with severe liver damage and abnormal liver regeneration in acetaminophen-induced liver injury

Abstract

Hepatic stellate cells (HSCs) are important part of the local 'stem cell niche' for hepatic progenitor cells (HPCs) and hepatocytes. However, it is unclear as to whether the products of activated HSCs are required to attenuate hepatocyte injury, enhance liver regeneration, or both. In this study, we performed 'loss of function' studies by depleting activated HSCs with gliotoxin. It was demonstrated that a significantly severe liver damage and declined survival rate were correlated with depletion of activated HSCs. Furthermore, diminishing HSC activation resulted in a 3-fold increase in hepatocyte apoptosis and a 66% decrease in the number of proliferating hepatocytes. This was accompanied by a dramatic decrease in the expression levels of five genes known to be up-regulated during hepatocyte replication. In particular, it was found that depletion of activated HSCs inhibited oval cell reaction that was confirmed by decreased numbers of Pank-positive cells around the portal tracts and lowered gene expression level of cytokeratin 19 (CK19) in gliotoxin-treated liver. These data provide clear evidence that the activated HSCs are involved in both hepatocyte death and proliferation of hepatocytes and HPCs in acetaminophen (APAP)-induced acute liver injury.

Smoothened is a master regulator of adult liver repair

“…justifies strategies that aim to prevent liver fibrosis by reducing hepatic epithelial injury, since success aborts production of Hh ligands that would otherwise provide a major paracrine stimulus for SMO activation in MFs and consequent MF accumulation and liver fibrosis. Third, evidence that hepatic accumulation of liver epithelial progenitors is blocked (and liver atrophy enhanced) by conditional deletion of SMO in MFs provides an explanation for previous observations that MF depletion impairs liver regeneration in adults (53,54) and implies that progenitors play a more important role in adult liver regeneration than generally believed. Fourth, proof that SMO-dependent signals are required for resident HSCs to become proliferative MFs, coupled with evidence that MF-HSCs express markers of multipotent progenitor cells, supports complementary lineage-tracing evidence that HSCs function as facultative progenitors to replace damaged liver epithelial cells in injured livers.…”

Hepatic stellate cells in liver development, regeneration, and cancer

“…Recent evidence also suggests that in progenitor cell-mediated liver regeneration, hepatic stellate cells may, through a process of mesenchymal to epithelial transition, give rise to hepatocytes (21). Supporting the involvement of stellate cells in liver regeneration, inhibiting activated hepatic stellate cells using gliotoxin (79) and l-cysteine (80) prevents normal regenerative responses of both hepatocytes and oval cells in acetaminophen and 2AAF/PH-induced liver injuries, respectively. In addition, Foxf1 +/-mice subjected to CCl 4 injury show decreased hepatic stellate cell activation and more severe hepatocyte necrosis during the regenerative period (81).…”

Liver Injury Models for Induction of Hepatic Oval Cells in Rodents

“…Oval cell responses are detected as early as 3 hours after injury and it is hypothesized that this rapid response is due to a centri-lobular form of injury [28]. For mice, APAP is given as a single intra-peritoneal dose between 25-100mg per 100g body weight [28,52] or in multiple doses at 30mg per 100g body weight [127].…”