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Dendritic cells regulate angiogenesis associated with liver fibrogenesis

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Abstract

During liver fibrogenesis the immune response and angiogenesis process are fine-tuned resulting in activation of hepatic stellate cells that produce an excess of extracellular matrix proteins. Dendritic cells (DC) play a central role modulating the liver immunity and have recently been implicated to favour fibrosis regression; although their ability to influence the development of fibrogenesis is unknown. Therefore, we explored whether the depletion of DC during early stages of liver injury has an impact in the development of fibrogenesis. Using the CD11c.DTR transgenic mice, DC were depleted in two experimental models of fibrosis in vivo. The effect of anti-angiogenic therapy was tested during early stages of liver fibrogenesis. DC depletion accelerates the development of fibrosis and as a consequence, the angiogenesis process is boosted. We observed up-regulation of pro-angiogenic factors together with an enhanced vascular endothelial growth factor (VEGF) bioavailability, mainly evidenced by the decrease of anti-angiogenic VEGF receptor 1 (also known as sFlt-1) levels. Interestingly, fibrogenesis process enhanced the expression of Flt-1 on hepatic DC and administration of sFlt-1 was sufficient to abrogate the acceleration of fibrogenesis upon DC depletion. Thus, DC emerge as novel players during the development of liver fibrosis regulating the angiogenesis process and thereby influencing fibrogenesis.

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Acknowledgments

The authors acknowledge financial support of their work by the bilateral cooperation project #01DN1207 between Ministerio de Ciencia y Tecnología (MICYT, Argentina) and Bundesministerium für Bildung und Forschung-Deutschen Zentrum für Luft und Raumfahrt (BMBF-DLR, Germany) to S.M.B. and M.G.G. This work was supported in part by research grants from Charité Stiftung to S.M.B. and Agencia Nacional de Promoción Científica y Tecnológica PICT#2010 to G.M. and M.G.G. F.P. was recipient of a short-scholarship from the German Academic Exchange Program (DAAD), N.F. is supported by Charité Doctoral-Stipendium and I.T.-G. by the Charité Habilitation-Fellowship.

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Authors and Affiliations

  1. Charité Center 12 Internal Medicine and Dermatology, Reproductive Medicine Research Group, Universitätsmedizin Berlin, Berlin, Germany

    Sandra M. Blois, Nancy Freitag, Irene Tirado-González, Petra Moschansky & Matthias Rose

  2. Zentrallabor Campus Virchow-Klinikum, Universitätsmedizin Berlin, Berlin, Germany

    Karin Hensel-Wiegel

  3. Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Presidente Perón 1500, B1629ODT, Derqui-Pilar, Buenos Aires, Argentina

    Flavia Piccioni, Rodrigo Lloyd, Mariana G. Garcia, Laura D. Alaniz & Guillermo Mazzolini

  4. CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina

    Flavia Piccioni, Rodrigo Lloyd, Mariana G. Garcia, Laura D. Alaniz & Guillermo Mazzolini

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  1. Sandra M. Blois
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  2. Flavia Piccioni
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  4. Irene Tirado-González
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  7. Karin Hensel-Wiegel
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  9. Mariana G. Garcia
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  10. Laura D. Alaniz
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  11. Guillermo Mazzolini
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Correspondence to Sandra M. Blois or Guillermo Mazzolini.

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Flavia Piccioni and Nancy Freitag have contributed equally to this work.

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Blois, S.M., Piccioni, F., Freitag, N. et al. Dendritic cells regulate angiogenesis associated with liver fibrogenesis. Angiogenesis 17, 119–128 (2014). https://doi.org/10.1007/s10456-013-9382-5

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  • DOI: https://doi.org/10.1007/s10456-013-9382-5

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