Oval Cell Response Is Attenuated by Depletion of Liver Resident Macrophages in the 2-AAF/Partial Hepatectomy Rat

Abstract

Background/AimsMacrophages are known to play an important role in hepatocyte mediated liver regeneration by secreting inflammatory mediators. However, there is little information available on the role of resident macrophages in oval cell mediated liver regeneration. In the present study we aimed to investigate the role of macrophages in oval cell expansion induced by 2-acetylaminofluorene/partial hepatectomy (2-AAF/PH) in rats.Methodology/Principal FindingsWe depleted macrophages in the liver of 2-AAF/PH treated rats by injecting liposome encapsulated clodronate 48 hours before PH. Regeneration of remnant liver mass, as well as proliferation and differentiation of oval cells were measured. We found that macrophage-depleted rats suffered higher mortality and liver transaminase levels. We also showed that depletion of macrophages yielded a significant decrease of EPCAM and PCK positive oval cells in immunohistochemical stained liver sections 9 days after PH. Meanwhile, oval cell differentiation was also attenuated as a result of macrophage depletion, as large foci of small basophilic hepatocytes were observed by day 9 following hepatectomy in control rats whereas they were almost absent in macrophage depleted rats. Accordingly, real-time polymerase chain reaction analysis showed lower expression of albumin mRNA in macrophage depleted livers. Then we assessed whether macrophage depletion may affect hepatic production of stimulating cytokines for liver regeneration. We showed that macrophage-depletion significantly inhibited hepatic expression of tumor necrosis factor-α and interleukin-6, along with a lack of signal transducer and activator of transcription 3 phosphorylation during the early period following hepatectomy.ConclusionsThese data indicate that macrophages play an important role in oval cell mediated liver regeneration in the 2-AAF/PH model.

Macrophages: Supportive cells for tissue repair and regeneration

“…Since LPC proliferation and apoptosis rates are not altered by macrophage depletion, this suggests that macrophages are required for the very early phase of LPC priming after acute injury to enter the cell cycle (Xiang et al, 2012). This hypothesis was further confirmed by a very smart study which deciphers some early signalling pathways the environment, including A c c e p t e d M a n u s c r i p t 8 macrophages, delivers to LPCs to induce them in the hepatocyte route.…”

“…Anyway, macrophage depletion induces a decrease in LPC number and impairment in their differentiation and maturation, as almost no formation of small hepatocyte-like cells being observed (Xiang et al, 2012). Since LPC proliferation and apoptosis rates are not altered by macrophage depletion, this suggests that macrophages are required for the very early phase of LPC priming after acute injury to enter the cell cycle (Xiang et al, 2012).…”

“…It promotes IL-10 production by macrophages, which in turn produce MMP-13 that is essential for functional recovery (Shechter et al, 2011). Similarly, substance P triggers and anti-inflammatory milieu in spinal cord injury, which induces IL-10 production by macrophages, and M a n u s c r i p t 13 the reduction of inducible nitric oxide synthase and TNFα synthesis (Jiang et al, 2012). In the same way, introducing anti-IL-6 antibodies switches macrophages from a haematogenous phenotype to a resident-microglial-like phenotype, which is associated with a decrease of pro-inflammatory markers and an increase in axonal regeneration and sprouting (Mukaino et al, 2010).…”

Wnt/β-Catenin Signaling in Liver Development, Homeostasis, and Pathobiology

“…Macrophage-derived Wnt3a induced canonical Wnt/β-catenin signaling in LPCs and promoted their differentiation to hepatocytes (151) (Figure 7 a ). In the rat AAF/PHx model, depletion of macrophages with clodronate prior to surgery resulted in a reduced oval cell response (204). However, in the CDE-diet model of liver injury, depletion of Kupffer cells via clodronate did not reduce oval cell proliferation in CDE-diet-fed mice but reduced oval cell invasion into the parenchyma (205).…”

Regulation of ERK and AKT Pathways by Hepatitis B Virus X Protein via Notch1 Pathway in Hepatocellular Carcinoma

“…fluorescence immunostaining was performed as described previously (18,19). Double-labeling immunofluorescence was used to detect HBx and Notch1 simultaneously.…”