Abstract
Homeostasis of solid tissue is characterized by a low proliferative activity of differentiated cells while special conditions like tissue damage induce regeneration and proliferation. For some cell types it has been shown that various tissue-specific functions are missing in the proliferating state, raising the possibility that their proliferation is not compatible with a fully differentiated state. While endothelial cells are important players in regenerating tissue as well as in the vascularization of tumors, the impact of proliferation on their features remains elusive. To examine cell features in dependence of proliferation, we established human endothelial cell lines in which proliferation is tightly controlled by a doxycycline-dependent, synthetic regulatory unit. We observed that uptake of macromolecules and establishment of cell–cell contacts was more pronounced in the growth-arrested state. Tube-like structures were formed in vitro in both proliferating and non-proliferating conditions. However, functional vessel formation upon transplantation into immune-compromised mice was restricted to the proliferative state. Kaposi’s sarcoma-associated herpes virus (KSHV) infection resulted in reduced expression of endothelial markers. Upon transplantation of infected cells, drastic differences were observed: proliferation arrested cells acquired a high migratory activity while the proliferating counterparts established a tumor-like phenotype, similar to Kaposi Sarcoma lesions. The study gives evidence that proliferation governs endothelial functions. This suggests that several endothelial functions are differentially expressed during angiogenesis. Moreover, since proliferation defines the functional properties of cells upon infection with KSHV, this process crucially affects the fate of virus-infected cells.
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Acknowledgements
This work was supported by Grants from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) within the Cluster of Excellence REBIRTH (From Regenerative Biology to Reconstructive Therapy), the SFB900 (Sonderforschungsbereich 900, chronic infection) and WI2648/3-1. We thank the Federal Ministry for Education and Research (BMBF) for support by funding the EBio project ImmunoQuant, FKZ0316170F. M. Butueva, C. Lipps and T. Dubich wish to acknowledge the support by the HZI GradSchool and the PhD program Regenerative Sciences within the Hannover Biomedical Research School (HBRS).
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Tobias May, Hansjörg Hauser and Dagmar Wirth have filed a patent concerning the technology for establishment of conditionally immortalized cell lines.
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C. Lipps, M. Badar and M. Butueva equally contributed.
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Lipps, C., Badar, M., Butueva, M. et al. Proliferation status defines functional properties of endothelial cells. Cell. Mol. Life Sci. 74, 1319–1333 (2017). https://doi.org/10.1007/s00018-016-2417-5
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DOI: https://doi.org/10.1007/s00018-016-2417-5