Vascular endothelial growth factor-stimulated cerebral microvascular endothelial cells mediate the recruitment of neural stem cells to the neurovascular niche.
Endogenous and transplanted neural stem cells (NSC) are highly migratory and display a unique tropism for areas of neuro-pathology. However, signals controlling NSC motility in health and disease are still ill-defined. NSC appear to be intimately associated with the cerebral vasculature and angiogenesis is a hallmark of many neurological disorders. This has led us to investigate the influence of quiescent and angiogenically active human endothelial cells on human NSC migration. In vivo we observed frequent perivascular accumulation of human NSC in the proximity of cerebral microvessels upon induction of angiogenesis by cerebral infusion of vascular endothelial growth factor (VEGF) into the murine brain. We analyzed the in vitro effects of conditioned media from human endothelial cells before and after angiogenic stimulation with VEGF on the migration of human NSC in vitro. Non-stimulated endothelial cells induced a moderate chemotactic migration that was significantly enhanced after angiogenic activation by VEGF. In order to identify cytokines that may function as stimulators of NSC chemotaxis, we screened endothelial cell-conditioned media for the expression of 120 different cytokines. We identified PDGF-BB, RANTES, I-TAC, NAP-2, GROalpha, Ang-2, and M-CSF as endothelial cell-released chemoattractants for human NSC in vitro. VEGF-stimulated cerebral microvascular endothelial cells secreted higher levels of Ang-2 and GROalpha, which in part were responsible for the enhanced chemoattraction of NSC. Our findings support the hypothesis that the angiogenically active microvasculature modulates the local guidance of NSC through endothelial cell-derived chemoattractants.
Schmidt
Nils O
NO
Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Electronic address: nschmidt@uke.uni-hamburg.de.
Koeder
Dennis
D
Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Messing
Markus
M
Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Mueller
Franz-Josef
FJ
ZIP-Kiel, Center for Psychiatry, University Hospital Schleswig Holstein Campus Kiel, Kiel, Germany.
Aboody
Karen S
KS
Divisions of Hematology/Hematopoietic Cell Transplantation and Neurosciences, City of Hope National Medical Center, Duarte, CA, USA.
Kim
Seung U
SU
Department of Medicine, University of British Columbia Hospital, University of British Columbia, Vancouver, Canada.
Black
Peter M
PM
Neurosurgical Oncology Lab, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Carroll
Rona S
RS
Neurosurgical Oncology Lab, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Westphal
Manfred
M
Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Lamszus
Katrin
K
Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D002540:Cerebral Cortex / Q000098:blood supply* / Q000502:physiology; D002633:Chemotaxis; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D055806:Microvessels / Q000166:cytology / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D055153:Stem Cell Niche / Q000166:cytology*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D016207:Cytokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A