Immunohistochemical characterization of glial fibrillary acidic protein (GFAP)-expressing cells in a rat liver cirrhosis model induced by repeated injections of thioacetamide (TAA)

Tennakoon, A.P.; Izawa, Takeshi; Wijesundera, Kavindra Kumara; Murakami, Hiroshi; Katou-Ichikawa, Chisa; Tanaka, Miyuu; Golbar, Hossain M.; Kuwamura, Mitsuru; Yamate, Jyoji

doi:10.1016/j.etp.2014.09.008

Cited by 26 publications

(38 citation statements)

References 46 publications

(53 reference statements)

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“…On the other hand, HSCs contribute to the pathogenesis of liver fibrosis by increasing production (fibrogenesis) and inhibiting degradation (fibrolysis) of ECM simultaneously in both DDC‐induced and TAA‐induced liver injury. HSCs were major contributors of the pathogenesis of liver fibrosis over Thy1‐expressing cells in models of toxic liver injury, consistent with other reports 34, 35. Therefore, we propose that Thy1 MCs, which represent PFs, contribute specifically to the pathogenesis of liver fibrosis in models of cholestatic liver injury whereas HSCs contribute to liver fibrosis in models of both cholestatic and toxic liver injury.…”

Section: Discussionsupporting

confidence: 91%

Portal fibroblasts marked by the surface antigen Thy1 contribute to fibrosis in mouse models of cholestatic liver injury

Katsumata

Miyajima

Itoh

2017

Hepatology Communications

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Liver fibrosis, a condition that is characterized by excessive production and accumulation of extracellular matrix, including collagen, is the most common outcome of chronic liver injuries of different etiologies. Vitamin A‐storing hepatic stellate cells (HSCs) are considered to be the main source of this collagen production, with activation in response to liver injury. In contrast, the contribution of other cell types to this fibrogenic response remains largely elusive due to the lack of specific surface markers to identify and isolate these cells for detailed analysis. Here, we identify a mesenchymal population of thymus cell antigen 1 (Thy1)+ CD45− cells (Thy1 MCs) in the mouse liver; these cells reside near the portal vein in vivo and indicate profibrogenic characteristics in vitro, shown by their expression of collagen and α‐smooth muscle actin. Flow cytometric analysis of mouse liver nonparenchymal cells revealed that vitamin A storage and Thy1 expression were mutually exclusive, indicating that Thy1 MCs are distinct from HSCs. Importantly, Thy1 MCs reacted and contributed to the development of liver fibrosis specifically in mouse models of cholestatic liver injury. With the occurrence of cholestatic liver injury, collagen‐producing Thy1 MCs expanded in cell number and inhibited collagen degradation through up‐regulation of matrix metalloproteinase inhibitor Timp1 expression, thereby promoting the accumulation of extracellular matrix in the periportal area. Conclusion: This study establishes Thy1 as a useful cell surface marker to prospectively identify and isolate periportal fibroblasts and further highlights a significant contribution of these cells to the pathogenesis of liver fibrosis caused by cholestatic liver injuries. We suggest that Thy1 MCs may be an interesting therapeutic target for treating liver fibrosis in addition to the well‐characterized HSCs. (Hepatology Communications 2017;1:198‐214)

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Section: Discussionsupporting

confidence: 91%

Portal fibroblasts marked by the surface antigen Thy1 contribute to fibrosis in mouse models of cholestatic liver injury

Katsumata

Miyajima

Itoh

2017

Hepatology Communications

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“…Apoptotic myofibroblasts are seen in the lesions of TAAinduced cirrhosis (Tennakoon et al 2015). This hypothesis is supported by a recent study showing that miR-214 downregulates connective tissue growth factor, thereby inhibiting myofibroblast differentiation and ECM production in humans and mice (Chen et al 2014).…”

Section: Discussionmentioning

confidence: 84%

Anti-fibrotic Role of miR-214 in Thioacetamide-induced Liver Cirrhosis in Rats

et al. 2015

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An increasing number of studies have focused on the role of microRNAs in liver fibrosis/cirrhosis. miR-214 has recently attracted more attention as a fibrosis-related factor; however, the molecular mechanisms in hepatic fibrogenesis remain largely unknown. Here, we investigate the pathological role of miR-214 during progression of liver cirrhosis in rats. Rats were injected intraperitoneally with thioacetamide at a dose of 100 mg/kg body weight, twice a week. The liver was collected at post first injection weeks 5, 10, 15, and 20. Hepatic expression of miR-214 was analyzed by real-time polymerase chain reaction, in situ hybridization, and laser microdissection. The effects of miR-214 overexpression were investigated by in vitro transfection using fibroblastic MT-9 cells. miR-214 was highly upregulated in the fibrotic area in parallel with the cirrhosis progression. miR-214 overexpression in MT-9 cells under transforming growth factor-β1 stimulation resulted in decreased cell number and increased expression of cleaved caspase 3 and decreased expression of α-smooth muscle actin, suggesting that miR-214 induces apoptosis and inhibits myofibroblast differentiation in fibroblastic cells under stimulation of fibrogenic factors. These data indicate an anti-fibrotic role of miR-214 in chemically induced liver fibrosis/cirrhosis.

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“…On the contrary, some DAMPs take part in fibrosis; particularly, HMGB-1 induces liver fibrosis through activating TLR-4 on Kupffer cells, and S-100 A4 acts as a factor activating hepatic stellate cells which can produce extracellular matrices 68,70) . Hepatic stellate cells are stimulated by M2-macrophage-producing factors such as TGF-β1, and the cells can transform into myofibroblasts capable of producing abundant collagens resulting in fibrosis 25,71,72) . Thus, M2-macrophages relating to fibrosis may be induced by such DAMPs.…”

Section: Damps and Mhc Class Ii-expressing Antigen-presenting Macrophmentioning

confidence: 99%

Histopathological Analysis of Rat Hepatotoxicity Based on Macrophage Functions: in Particular, an Analysis for Thioacetamide-induced Hepatic Lesions

2016

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Hepatic macrophages play an important role in homeostasis. The functional abnormalities of hepatic macrophages primarily or secondarily influence chemically induced hepatotoxicity. However, the evaluation system based on their functions has not yet been established. Recently, a new concept (M1-/M2-macrophage polarization) was proposed; M1macropahges are induced by INF-γ, and show high phagocytosis/tissue damage, whereas M2-macropahges are induced by IL-4 and play roles in reparative fibrosis by releasing IL-10 and TGF-β1. In hepatogenesis, CD68-expressing M1macrophages predominantly exist in embryos; in neonates, in contrast, CD163-/CD204-expressing M2-macrophages appear along the sinusoids and mature as Kupffer cells. Activated Kupffer cells by liposome decrease AST and ALT values, whereas AST and ALT values are increased under Kupffer cells depleted with clodronate treatment. Since Kupffer cells may be involved in clearance of liver enzymes, macrophage condition should be taken into consideration when hepatotoxicity is analyzed. In TAA-induced acute hepatic lesions, INF-γ, TNF-α and IL-6 for M1-factors and IL-4 for M2factors are already increased before histopathological change; the appearance of CD68-expressing M1-macrophages and CD163-expressing M2-macrophages follows in injured centrilobular lesions, and TGF-β1 and IL-10 are increased for reparative fibrosis. CD68-expressing M1-macrophages co-express MHC class II and Iba-1, whereas CD163-expressing M2-macrophages also express CD204 and Galectin-3. Under macrophage depletion by clodoronate, TAA-treated rat livers show prolonged coagulation necrosis of hepatocytes, and then develop dystrophic calcification without reparative fibrosis. The depletion of hepatic macrophages influences hepatic lesion development. Collectively, a histopathological analysis method for hepatotoxicity according to M1-/M2-macrophage polarization would lead to the refinement of hazard characterization of chemicals in food and feed.

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Immunohistochemical characterization of glial fibrillary acidic protein (GFAP)-expressing cells in a rat liver cirrhosis model induced by repeated injections of thioacetamide (TAA)

Cited by 26 publications

References 46 publications

Portal fibroblasts marked by the surface antigen Thy1 contribute to fibrosis in mouse models of cholestatic liver injury

Portal fibroblasts marked by the surface antigen Thy1 contribute to fibrosis in mouse models of cholestatic liver injury

Anti-fibrotic Role of miR-214 in Thioacetamide-induced Liver Cirrhosis in Rats

Histopathological Analysis of Rat Hepatotoxicity Based on Macrophage Functions: in Particular, an Analysis for Thioacetamide-induced Hepatic Lesions

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