Pleiotrophin/Heparin-Binding Growth-Associated Molecule as a Mitogen of Rat Hepatocytes and Its Role in Regeneration and Development of Liver

Asahina, Kinji; Sato, Hajime; Yamasaki, Chihiro; Kataoka, Mikiko; Shiokawa, Miho; Katayama, Shigeru; Tateno, Chise; Yoshizato, Katsutoshi

doi:10.1016/s0002-9440(10)61167-4

Cited by 80 publications

(84 citation statements)

References 45 publications

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“…Especially the role of HSCs in the hepatic fibrogenesis and carcinogenesis has been a major issue among investigators [32]. Previously, we showed that HSCderived PTN plays a role as a hepatocytes growth factor [6,9]. Furthermore, we showed that PTN expression was increased in CCl 4 -induced fibrotic liver [10], suggesting the involvement of PTN in hepatic fibrogenesis, to which TGFb1 is also committed as an anti-hepatocyte growth factor and an ECMformation accelerator.…”

Section: Discussionmentioning

confidence: 97%

“…PTN is an 18 kDa heparin binding protein and shows 50% identity to midkine (MK) [2][3][4]. It promotes the growth of fibroblasts, endothelial cells, and hepatocytes [4][5][6]. Its gene is grouped as a potent proto-oncogene [7][8].…”

Section: Introductionmentioning

confidence: 99%

“…When co-cultured, rat hepatic stellate cells (HSCs) enhanced the growth of rat hepatocytes by secreting PTN [6]. Furthermore, PTN expression was increased in carbon tetrachloride (CCl 4 )-induced fibrotic liver [10].…”

Section: Introductionmentioning

confidence: 99%

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Pleiotrophin inhibits transforming growth factor β1‐induced apoptosis in hepatoma cell lines

Park

Jeong

Tateno³

et al. 2008

Molecular Carcinogenesis

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Pleiotrophin (PTN) is a hepatocyte growth factor and considered to play roles in liver fibrogenesis and hepatocarcinogenesis. In this study we examined the mechanism of the action of PTN in these pathological processes. First, we confirmed that hepatic stellate cells (HSCs) and Kupffer cells, and also later hepatocytes in hyperplastic nodules increased PTN mRNA expressions during carbon tetrachloride-induced liver fibrosis. Then, the relationship between PTN and transforming growth factor b1 (TGFb1), a known potent pro-fibrogenetic cytokine, in carcinogenesis was investigated using hepatoma cell lines. Huh-7 human hepatoma cells weakly expressed PTN, but HepG2 human hepatoma cells and FaO rat hepatoma cells did not. Recombinant (r) TGFb1 induced the cultured Huh-7 cells to undergo apoptosis, which was inhibited by rPTN. Huh-7 cells became resistant to TGFb1-, but not mitomycin C-induced apoptosis when transfected with PTN gene, indicating the specificity of the PTN anti-apoptotic activity. Poly ADP ribose polymerase, procaspase-8 and procaspase-3 were not cleaved in the TGFb1-reluctant cells. The TGFb1-induced caspase-3 activation was also suppressed in Huh-7 and FaO cells both transduced with PTN gene-bearing adenoviruses. In summary, PTN was expressed in HSCs, Kupffer cells, and hepatocytes in fibrotic liver. We propose that PTN specifically antagonizes the TGFb1 activity during liver fibrosis. ß

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Pleiotrophin inhibits transforming growth factor β1‐induced apoptosis in hepatoma cell lines

Park

Jeong

Tateno³

et al. 2008

Molecular Carcinogenesis

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“…Conditional cell lineage tracing using Wt1 CreERT2 ; Rosa26 flox (R26 f ) reporter mice demonstrated that the Wt1 + mesothelium migrates inward from the liver surface and gives rise to hepatic stellate cells (HSCs), fibroblasts, and smooth muscle cells during liver morphogenesis (8). In addition, embryonic MCs may support proliferation of hepatoblasts by secretion of hepatocyte growth factor (HGF) and pleiotrophin (PTN) (9,10). These results indicate that MCs are progenitor cells of liver mesenchymal cells and play a role in hepatogenesis.…”

mentioning

confidence: 99%

Mesothelial cells give rise to hepatic stellate cells and myofibroblasts via mesothelial–mesenchymal transition in liver injury

Wang

Asahina

2013

Proc. Natl. Acad. Sci. U.S.A.

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In many organs, myofibroblasts play a major role in the scarring process in response to injury. In liver fibrogenesis, hepatic stellate cells (HSCs) are thought to transdifferentiate into myofibroblasts, but the origins of both HSCs and myofibroblasts remain elusive. In the developing liver, lung, and intestine, mesothelial cells (MCs) differentiate into specific mesenchymal cell types; however, the contribution of this differentiation to organ injury is unknown. In the present study, using mouse models, conditional cell lineage analysis has demonstrated that MCs expressing Wilms tumor 1 give rise to HSCs and myofibroblasts during liver fibrogenesis. Primary MCs, isolated from adult mouse liver using antibodies against glycoprotein M6a, undergo myofibroblastic transdifferentiation. Antagonism of TGF-β signaling suppresses transition of MCs to mesenchymal cells both in vitro and in vivo. These results indicate that MCs undergo mesothelial–mesenchymal transition and participate in liver injury via differentiation to HSCs and myofibroblasts.

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“…The influence of liver regeneration, especially regeneration after partial hepatectomy, on other functions of HSCs has been examined from various aspects. For example, the start point of DNA synthesis of HSCs (Tanaka et al, 1990); alterations in the amounts of protein products, including cytokines, enzymes, and transcription factors (Marsden et al, 1992;Watanabe et al, 1998;Ujiki et al, 2000;Asahina et al, 2002); and cell-cell interactions between HSCs and hepatocytes (Mabuchi et al, 2004) have been already assessed in the regenerating liver after 70% PHx. The fact that hepatocyte-HSC interaction in the early stages after PHx (1-3 days) is intimately involved in the regeneration process (Mabuchi et al, 2004) has particularly shown the importance of the role of HSCs during liver regeneration (Balabaud et al, 2004).…”

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confidence: 99%

Vitamin A storage in hepatic stellate cells in the regenerating rat liver: With special reference to zonal heterogeneity

et al. 2005

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Under physiological conditions, hepatic stellate cells (HSCs) within liver lobules store about 80% of the total body vitamin A in lipid droplets in their cytoplasm, and these cells show zonal heterogeneity in terms of vitamin A-storing capacity. Vitamin A is essential for the growth and differentiation of cells, and it is well known that liver cells including HSCs show a remarkable growth capacity after partial hepatectomy (PHx). However, the status of vitamin A storage in HSCs in the liver regeneration is not yet known. Therefore, we conducted the present study to examine vitamin A storage in these cells during liver regeneration. Morphometry at the electron microscopic level, fluorescence microscopy for vitamin A autofluorescence, and immunofluorescence microscopy for desmin and ␣-smooth muscle actin (␣-SMA) were performed on sections of liver from male Wistar strain rats at various times after the animal had been subjected to 70% PHx. The mean area of vitamin A-storing lipid droplets per HSC gradually decreased toward 3 days after PHx, and then returned to normal within 14 days after it. However, the heterogeneity of vitamin A-storing lipid droplet area per HSC within the hepatic lobule disappeared after PHx and did not return to normal by 14 days thereafter, even though the liver volume had returned to normal. These results suggest that HSCs alter their vitamin A-storing capacity during liver regeneration and that the recovery of vitamin A homeostasis requires a much longer time than that for liver volume.

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Pleiotrophin/Heparin-Binding Growth-Associated Molecule as a Mitogen of Rat Hepatocytes and Its Role in Regeneration and Development of Liver

Cited by 80 publications

References 45 publications

Pleiotrophin inhibits transforming growth factor β1‐induced apoptosis in hepatoma cell lines

Pleiotrophin inhibits transforming growth factor β1‐induced apoptosis in hepatoma cell lines

Mesothelial cells give rise to hepatic stellate cells and myofibroblasts via mesothelial–mesenchymal transition in liver injury

Vitamin A storage in hepatic stellate cells in the regenerating rat liver: With special reference to zonal heterogeneity

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