Einfluss des extrazellulären Matrixproteins Fibronektin auf die Entwicklung einer Leberfibrose
Zusammenfassung der Projektergebnisse
Liver fibrosis develops when an insult to the liver results in release of the profibrotic substance TGF-b and accumulation of extracellular matrix proteins leading to liver function impairment. The matrix consists of several proteins most notably fibronectin and collagen. These matrix proteins modify the behavior of the cell types embedded in them by acting on cell surface receptors called integrins. We therefore modified the matrix composition as well as the presence of key integrins genetically and pharmaceutically in vitro and in vivo. The lessons learned can be summarized as follows: While deletion of fibronectin in stellate cells enhances fibrosis and is thus detrimental, decreasing it pharmacologically diminishes fibrosis, possibly in part by decreasing immune cell infiltration. In line with this, decreasing collagen accumulation pharmacologically also diminishes fibrosis, but in this case it affected TGF-b amount in the matrix. In parallel, we found that deletion of b1 integrin, the main integrin subunit that binds fibronectin and collagen leads to increased TGF-b and increased fibrosis. While these data are at face value contradictory, we hypothesized that the molecule we used to prevent collagen accumulation includes a sequence able to suppress TGF-b and diminish fibrosis. Based on this we were able to identify a critical 5 amino acid sequence, which we further modified to produce a molecule that acts on a11b1 integrin diminishing TGF-b and collagen production. Testing it in vivo revealed a marked suppression of matrix accumulation and liver fibrosis. Preliminary results in a tumor model are promising. Because of the promising results in cancer, however, we will confirm the results in cancer and evaluate the efficacy in a lung fibrosis model.
Projektbezogene Publikationen (Auswahl)
- “Complement activation correlates with liver necrosis and fibrosis in chronic hepatitis C”. Clin Immunol. 2014 Feb;150(2):149-56
M. Vasel, R. Rutz, C. Bersch, P. Feick, MV. Singer, M. Kirschfink, I. A. Nakchbandi
(Siehe online unter https://doi.org/10.1016/j.clim.2013.11.014) - “Inhibition of fibronectin deposition improves experimental liver fibrosis”. J Hepatol. 2015 Mar;62(3):625-33. Erratum in: J Hepatol. 2015 Jun;62(6):1455-6
E. Altrock, C. Sens, C. Würfel, M. Vasel, N. Kawelke, S. Dooley, J. Sottile, I.A. Nakchbandi
(Siehe online unter https://doi.org/10.1016/j.jhep.2014.06.010) - “EDA-Fibronectin Originating from Osteoblasts Inhibits the Immune Response against Cancer”. 2016; PLoS Biol 14(9):e1002562
S. Rossnagl, E. Altrock, C. Sens, S. Kraft, K. Rau, M.D. Milsom, T. Giese, Y. Samstag, I.A. Nakchbandi
(Siehe online unter https://doi.org/10.1371/journal.pbio.1002562) - “An O-Glycosylation of Fibronectin Mediates Hepatic Osteodystrophy Through a4b1 Integrin”. J Bone Miner Res. 2017 Jan;32(1):70-81
C. Sens, E. Altrock, K. Rau, V. Klemis, S. Pettera, S. Uebel, M. Moser, I.A. Nakchbandi
(Siehe online unter https://doi.org/10.1002/jbmr.2916) - “Circulating fibronectin contributes to mesangial expansion in a murine model of type 1 diabetes”. Kidney Int. 2017 Jun;91(6):1374-1385
V. Klemis, H. Ghura, G. Frederico, C. Würfel, A. Bentmann, N. Gretz, T. Miyazaki, H.- J. Gröne, I.A. Nakchbandi
(Siehe online unter https://doi.org/10.1016/j.kint.2016.12.006)
