Mesenchymal stem cells regulate angiogenesis according to their mechanical environment

¹ Musculoskeletal Research Center Berlin, Charité - Universitätsmedizin, Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin, Berlin, Germany
² Musculoskeletal Research Center Berlin, Charité - Universitätsmedizin, Berlin, Germany
³ Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin, Berlin, Germany
⁴ Free University Berlin, Department of Biology, Chemistry, Pharmacy, Berlin, Germany; Musculoskeletal Research Center Berlin, Charité - Universitätsmedizin, Berlin, Germany
⁵ University for Technologies, Medical Biotechnology Department, Berlin, Germany

^* To whom correspondence should be addressed. E-mail: grit.kasper{at}charite.de.

	Abstract

In fracture and bone defect healing mesenchymal stem cells (MSCs) drive largely tissue regeneration. MSCs have been shown to promote angiogenesis both in vivo and in vitro. Angiogenesis is a prerequisite to large tissue reconstitution. The present study investigated how mechanical loading of MSCs influences their pro-angiogenic capacity. The results show a significant enhancement of angiogenesis by conditioned media from mechanically stimulated compared to unstimulated MSCs in 2D tube formation and 3D spheroid sprouting assays. In particular, proliferation, but not migration or adhesion of endothelial cells was elevated. Promotion of angiogenesis was dependent upon FGFR1 signalling. Moreover, stimulation of tube formation was inhibited by VEGFR tyrosine kinase blocking. Screening for the expression levels of different soluble regulators of angiogenesis revealed an enrichment of MMP-2, TGF-1 and bFGF, but not of VEGF in response to mechanical stimulation. In conclusion, mechanical loading of MSCs seems to result in a paracrine stimulation of angiogenesis most likely by the regulation of a network of several angiogenic molecules. The underlying mechanism appears to be dependent on the FGFR and VEGFR signalling cascades, and might be mediated by an additional cross talk with other pathways.

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