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.
Highlights
Under conditions where proliferation of mature hepatocytes is inhibited, liver progenitor cells, known as oval cells (OCs), expand and differentiate into mature hepatocytes and biliary epithelial cells in order to regenerate liver mass following hepatic damage
These data indicate that macrophages play an important role in oval cell mediated liver regeneration in the 2AAF/partial hepatectomy (PH) model
We investigated the specific contribution of macrophages on OC mediated liver regeneration
Summary
Under conditions where proliferation of mature hepatocytes is inhibited, liver progenitor cells, known as oval cells (OCs), expand and differentiate into mature hepatocytes and biliary epithelial cells in order to regenerate liver mass following hepatic damage. Liver progenitor cells are generally acknowledged to be involved in many human liver diseases and experimental animal models [1,2,3,4]. Stem cell therapy has promise as a new approach for treating life-threatening liver disease. Attention has recently focused on elucidating the responses and mechanisms involved in the activation and expansion of liver progenitor cells. The microenvironment is highly regulated within an organ and plays an important role in maintaining stem cell division under signaling modulation [8]. Innate immune cells and inflammatory processes have been reported to play an important role in OC dependent liver regeneration [9,10,11,12]
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