A novel mouse model of depletion of stellate cells clarifies their role in ischemia/reperfusion- and endotoxin-induced acute liver injury

Abstract

Background & Aims Hepatic stellate cells (HSCs) that express glial fibrillary acidic protein (GFAP) are located between the sinusoidal endothelial cells and hepatocytes. HSCs are activated during liver injury and cause hepatic fibrosis by producing excessive extracellular matrix. HSCs also produce many growth factors, chemokines and cytokines, and thus may play an important role in acute liver injury. However, this function has not been clarified due to unavailability of a model in which HSCs are depleted from the normal liver. Methods We treated mice expressing HSV-thymidine kinase under the GFAP promoter (GFAP-Tg) with 3 consecutive (3 days apart) CCl4 (0.16 μl/g; ip) injections to stimulate HSCs to enter the cell cycle and proliferate. This was followed by 10-day ganciclovir (40 μg/g/day; ip) treatment, which is expected to eliminate actively proliferating HSCs. Mice were then subjected to hepatic ischemia/reperfusion (I/R) or endotoxin treatment. Results CCl4/ganciclovir treatment caused depletion of the majority of HSCs (about 64-72%), while the liver recovered from the initial CCl4-induced injury (confirmed by histology, serum ALT and neutrophil infiltration). The magnitude of hepatic injury due to I/R or endotoxemia (determined by histopathology and serum ALT) was lower in HSC-depleted mice. Their hepatic expression of TNF-α, neutrophil chemoattractant CXCL1 and endothelin-A receptor also was significantly lower than the control mice. Conclusions HSCs play an important role both in I/R- and endotoxin-induced acute hepatocyte injury, with TNF-α and endothelin-1 as important mediators of these effects.

Hepatic Stellate Cells Play a Functional Role in Exacerbating Ischemia-Reperfusion Injury in Rat Liver

“…Endothelin (ET)-1 has been reported to induce contraction of quiescent HSCs [34], and thus ET-1 might be involved in the mechanism. Regarding this issue, Stewart et al [35] depleted HSCs from the liver using an insertion of the herpes simplex virus thymidine kinase gene under the GFAP promoter in mice. The degree of liver damage due to I/R was lower in the HSC-depleted mice than in control mice.…”

Pathogenesis of Kupffer Cells in Cholestatic Liver Injury

“…73 Another study has shown that HSC depletion attenuates liver damage and TNF-a production caused by ischemia/reperfusion or LPS. 74 There is also an implication that 42% of HSCs are vicinal to Kupffer cells in the liver, and these two cells may interact or communicate with each other for responses against liver injury, although further studies are required for conclusion. 75 These earlier findings suggest that Kupffer cells and HSCs may orchestrate in signaling and cytokine secretion during liver diseases.…”

Stellate Cell Depletion Models

“…The authors concluded that HMs were not only the professional scar-forming cells of the liver but also played a key role in the amplification of acute liver injury. In a follow-up publication the GFAP HSV-Tk (TG) mouse was used to investigate the role of HMs in ischemic reperfusion (IR) and bacterial sepsis (endotoxin exposure) [65]. Acute liver injury was induced by administering CCl 4 daily over 3 consecutive days to promote activation and proliferation of HMs then subjected mice to IR or endotoxin treatment.…”