Die Bedeutung von WISP1 für Leberregeneration, Proliferation und Überleben von Hepatozyten
Zusammenfassung der Projektergebnisse
The mechanisms underlying the remarkable capacity of the liver to regenerate are still not completely understood. Particularly, the cross talk between cytokines and cellular components of the process are of outmost importance because they represent potential avenues for diagnostics and therapeutics. Our investigations indicate that WISP1 is a direct target of TGF-β, a critical cytokine in wound healing processes. Additionally, WISP1 is strongly secreted by hepatocytes upon TGF-β stimulation. We were able to discard a direct role of WISP1 in resident liver cells (e.g. hepatocytes and non-parenchymal cells) based on our in vitro studies. However, the inflammatory context in which WISP1 induction is observed clearly indicates that this cytokine might play an important role in inflammation. To thoroughly investigate this, we currently use the knockout mouse model established in this project. An unexpected surprise came from the lack of response in hepatocytes and non-parenchymal cells to a relatively high concentration of recombinant WISP1 in vitro. However, this is not at all disappointing; since the complexity of liver tissue is not fully reflected in isolated cells. We believe that a convincing proof of a role for WISP1 in the process of liver damage and regeneration will be found in vivo with the now established knockout mouse.
Projektbezogene Publikationen (Auswahl)
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Phenotype and growth behavior of residual β-catenin-positive hepatocytes in livers of β-catenin-deficient mice. Histochem Cell Biol. 2010 Nov;134(5):469-81
Braeuning A, Singh Y, Rignall B, Buchmann A, Hammad S, Othman A, vonRecklinghausen I, Godoy P, Hoehme S, Drasdo D, Hengstler JG, Schwarz M
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Reversible manipulation of apoptosis sensitivity in cultured hepatocytes by matrix-mediated manipulation of signaling activities. Methods Mol Biol. 2010;640:139-55
Godoy P, Schug M, Bauer A, Hengstler JG
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Transcription factors ETF, E2F, and SP-1 are involved in cytokine-independent proliferation of murine hepatocytes. Hepatology. 2010 Dec;52(6):2127-36
Zellmer S, Schmidt-Heck W, Godoy P, Weng H, Meyer C, Lehmann T, Sparna T,Schormann W, Hammad S, Kreutz C, Timmer J, von Weizsäcker F, Thürmann PA, Merfort I, Guthke R, Dooley S, Hengstler JG, Gebhardt R
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Aphysiologically based toxicokinetic modelling approach to predict relevantconcentrations for in vitro testing. Arch Toxicol. 2011 Jun;85(6):555-63
Mielke H, Anger LT, Schug M, Hengstler JG, Stahlmann R, Gundert-Remy U
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Augmenter of liver regeneration (ALR) protects human hepatocytes against apoptosis. Biochem Biophys Res Commun. 2011 Jan 7;404(1):148-52
Ilowski M, Kleespies A, de Toni EN, Donabauer B, Jauch KW, Hengstler JG, Thasler WE
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Distinct role of endocytosis for Smad and non-Smad TGF-β signaling regulation in hepatocytes. J Hepatol. 2011 Aug;55(2):369-78
Meyer C, Godoy P, Bachmann A, Liu Y, Barzan D, Ilkavets I, Maier P, Herskind C, Hengstler JG, Dooley S
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Phenotype of single hepatocytesexpressing an activated version of β-catenin in liver of transgenic mice. J Mol Histol. 2011 Oct;42(5):393-400
Schreiber S, Rignall B, Braeuning A, Marx-Stoelting P, Ott T, Buchmann A,Hammad S, Hengstler JG, Schwarz M, Köhle C
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Decrease of global Methylation improves significantly hepatic Differentiation of Ad-MSCs: Possible future Application for Urea Detoxification. Cell Transplant. 2012 Apr 10
Seeliger C, Culmes M, Schyschka L, Yan X, Damm G, Wang Z, Kleeff J, Thasler WE, Hengstler J, Stöckle U, Ehnert S, Nussler AK
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Human hepatocytes: isolation, culture, and quality procedures. Methods Mol Biol. 2012;806:99-120
Knobeloch D, Ehnert S, Schyschka L, Büchler P, Schoenberg M, Kleeff J, Thasler WE, Nussler NC, Godoy P, Hengstler J, Nussler AK
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In vitro - in vivo correlation of gene expression alterations induced by liver carcinogens. Curr Med Chem. 2012;19(11):1721-30
Heise T, Schug M, Storm D, Ellinger-Ziegelbauer H, Ahr HJ, Hellwig B, Rahnenfuhrer J, Ghallab A, Guenther G, Sisnaiske J, Reif R, Godoy P, Mielke H,Gundert-Remy U, Lampen A, Oberemm A, Hengstler JG
