Mesenchymal stem cells regulate angiogenesis according to their mechanical environment.
In fracture and bone defect healing, MSCs largely drive 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 proangiogenic capacity. The results show a significant enhancement of angiogenesis by conditioned media from mechanically stimulated compared with unstimulated MSCs in two-dimensional tube formation and three-dimensional spheroid sprouting assays. In particular, proliferation but not migration or adhesion of endothelial cells was elevated. Promotion of angiogenesis was dependent upon fibroblast growth factor receptor 1 (FGFR1) signaling. Moreover, stimulation of tube formation was inhibited by vascular endothelial growth factor receptor (VEGFR) tyrosine kinase blocking. Screening for the expression levels of different soluble regulators of angiogenesis revealed an enrichment of matrix metalloprotease 2, transforming growth factor beta1, and basic fibroblast growth factor but not of vascular endothelial growth factor 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 signaling cascades and might be mediated by an additional cross-talk with other pathways.
Kasper
Grit
G
Musculoskeletal Research Center Berlin, Charité-Universitätsmedizin Berlin, Augustenburger Platz, 113353 Berlin, Germany. Grit.Kasper@charite.de
Dankert
Niels
N
Tuischer
Jens
J
Hoeft
Moritz
M
Gaber
Timo
T
Glaeser
Juliane D
JD
Zander
Desiree
D
Tschirschmann
Miriam
M
Thompson
Mark
M
Matziolis
Georg
G
Duda
Georg N
GN
D019644:Arthroplasty, Replacement, Hip; D019149:Bioreactors; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D002455:Cell Division; D003470:Culture Media; D005434:Flow Cytometry; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000502:physiology; D012038:Regeneration; D015398:Signal Transduction / Q000502:physiology
D003470:Culture Media; D017468:Receptors, Fibroblast Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor