Pleiotrophin as a Swiss 3T3 Cell-Derived Potent Mitogen for Adult Rat Hepatocytes

Sato, Hajime; Funahashi, Makoto; Kristensen, Dan Bach; Tateno, Chise; Yoshizato, Katsutoshi

doi:10.1006/excr.1998.4304

Cited by 42 publications

(49 citation statements)

References 27 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%

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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%

“…Previously we identified PTN as a mitogen for rat hepatocytes [9] among proteins secreted by Swiss 3T3 fibroblasts, indicating that PTN plays a role as a hepatocyte growth factor. When co-cultured, rat hepatic stellate cells (HSCs) enhanced the growth of rat hepatocytes by secreting PTN [6].…”

Section: Introductionmentioning

confidence: 95%

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

Park

Jeong

Tateno³

et al. 2008

Molecular Carcinogenesis

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“…However, we have identified a second cleavage site of the signal peptide leading to a 3-amino acid extension AEA (HARP 139 ), which seemed to be associated to its mitogenic activity (16,27). Similarly, discrepancies between results of previous studies were observed for the putative C-terminal maturation of HARP (21,28).…”

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confidence: 78%

“…As mentioned in the introduction, truncated forms of HARP at the C-terminal region have been identified in SW13 transfected with HARP cDNA and in Swiss 3T3 cells (21,28). Involvement of this C-terminal maturation in HARP mitogenic activity has not been clearly established, and, to further investigate this point, C-terminal truncated HARP proteins were produced in CHO-K1 cells.…”

Section: Involvement Of C-terminal Determinants For the Mitogenic Actmentioning

confidence: 99%

The Lysine-rich C-terminal Tail of Heparin Affin Regulatory Peptide Is Required for Mitogenic and Tumor Formation Activities

Bernard‐Pierrot

Delbé

Caruelle

et al. 2001

Journal of Biological Chemistry

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Heparin affin regulatory peptide (HARP) is a 18-kDa heparin-binding polypeptide that is highly expressed in developing tissues and in several primary human tumors. It seems to play a key role in cellular growth and differentiation. In vitro, HARP displays mitogenic, angiogenic, and neurite outgrowth activities. It is a secreted protein that is organized in two ␤-sheet domains, each domain containing a cluster of basic residues. To assess determinants involved in the biological activities of HARP, C-terminally truncated proteins were produced in Chinese hamster ovary-K1 cells and tested for their mitogenic, tumor formation in nude mice and neurite outgrowth activities. Our data clearly indicate that the residues 111-136 of the lysine-rich C-terminal domain are involved in the mitogenic and tumor formation activities of HARP. Correlatively, no signal transduction was detected using the corresponding mutant, suggesting the absence of HARP binding to its high affinity receptor. However, this C-terminal domain of HARP is not involved in the neurite outgrowth activity. We also demonstrate that HARP signal peptide cleavage could led to two maturated forms that are both but differentially mitogenic.

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“…Co-culturing hepatocytes with non-parenchymal cells is also reported to be useful in enhancing and maintaining hepatic functions in vitro (Sato et al, 1999;Sudo et al, 2004). Various culture systems can be investigated by utilizing the oxygen permeability through the bottom PDMS surface, such as the co-culture of hemispheroidal hepatocytes with non-parenchymal cells and double-layered co-cultures with the small intestinal cell line, Caco-2, using a cell culture insert to mimic the absorption and the metabolism in the small intestine and the liver tissue in vivo (Choi et al, 2004;Sakai et al, 2003).…”

Section: Discussionmentioning

confidence: 98%

Stable immobilization of rat hepatocytes as hemispheroids onto collagen‐conjugated poly‐dimethylsiloxane (PDMS) surfaces: Importance of direct oxygenation through PDMS for both formation and function

Nishikawa

Yamamoto

Kojima

et al. 2007

Biotech & Bioengineering

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The highly oxygen-permeable material, poly-dimethylsiloxane (PDMS), has the potential to be applied to cell culture microdevices, but cell detachment from PDMS has been a major problem. In this study, we demonstrate that a combination of collagen covalently immobilized PDMS and an adequate oxygen supply enables the establishment of a stable, attached spheroid (hemispheroid) culture of rat hepatocytes. The bottom PDMS surfaces were first treated with oxygen plasma, then coupled with aminosilane followed by a photoreactive crosslinker, and they were finally reacted with a collagen solution. X-ray photoelectron spectroscopy (XPS) and contact angle measurements showed that the covalent immobilization of collagen on the surface occurred only where the crosslinker had been introduced. On the collagen-conjugated PDMS surface, rat hepatocytes organized themselves into hemispheroids and maintained the viability and a remarkably high albumin production at least for 2 weeks of culture. In contrast, hepatocytes on the other types of PDMS surfaces formed suspended spheroids that had low albumin production. In addition, we showed that blocking the oxygen supply through the bottom PDMS surface inhibited the formation of hemispheroids and the augmentation of hepatocellular function. These results show that appropriate surface modification of PDMS is a promising approach towards the development of liver tissue microdevices.

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Pleiotrophin as a Swiss 3T3 Cell-Derived Potent Mitogen for Adult Rat Hepatocytes

Cited by 42 publications

References 27 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

The Lysine-rich C-terminal Tail of Heparin Affin Regulatory Peptide Is Required for Mitogenic and Tumor Formation Activities

Stable immobilization of rat hepatocytes as hemispheroids onto collagen‐conjugated poly‐dimethylsiloxane (PDMS) surfaces: Importance of direct oxygenation through PDMS for both formation and function

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