title: VEGF preconditioning leads to stem cell remodeling and attenuates age-related decay of adult hippocampal neurogenesis.
abstract: Several factors are known to enhance adult hippocampal neurogenesis but a factor capable of inducing a long-lasting neurogenic enhancement that attenuates age-related neurogenic decay has not been described. Here, we studied hippocampal neurogenesis following conditional VEGF induction in the adult brain and showed that a short episode of VEGF exposure withdrawn shortly after the generation of durable new vessels (but not under conditions where newly made vessels failed to persist) is sufficient for neurogenesis to proceed at a markedly elevated level for many months later. Continual neurogenic increase over several months was not accompanied by accelerated exhaustion of the neuronal stem cell (NSC) reserve, thereby allowing neurogenesis to proceed at a markedly elevated rate also in old mice. Neurogenic enhancement by VEGF preconditioning was, in part, attributed to rescue of age-related NSC quiescence. Remarkably, VEGF caused extensive NSC remodelling manifested in transition of the enigmatic NSC terminal arbor onto long cytoplasmic processes engaging with and spreading over even remote blood vessels, a configuration reminiscent of early postnatal "juvenile" NSCs. Together, these findings suggest that VEGF preconditioning might be harnessed for long-term neurogenic enhancement despite continued exposure to an "aged" systemic milieu.
authors.affiliation: Department of Developmental Biology and Cancer Research, Faculty of Medicine, The Hebrew University, Jerusalem 91120, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Licht
authors.affiliation: Department of Developmental Biology and Cancer Research, Faculty of Medicine, The Hebrew University, Jerusalem 91120, Israel.
authors.forename: Gadiel
authors.initials: G
authors.lastname: Rothe
authors.affiliation: Department of Developmental Biology and Cancer Research, Faculty of Medicine, The Hebrew University, Jerusalem 91120, Israel.
authors.forename: Tirzah
authors.initials: T
authors.lastname: Kreisel
authors.affiliation: Department of Developmental Biology and Cancer Research, Faculty of Medicine, The Hebrew University, Jerusalem 91120, Israel.
authors.forename: Brachi
authors.initials: B
authors.lastname: Wolf
authors.affiliation: School of Pharmacy, Institute for Drug Research, Faculty of Medicine, The Hebrew University, Jerusalem 91120, Israel.
authors.forename: Ofra
authors.initials: O
authors.lastname: Benny
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh EH16 4UU, United Kingdom.
authors.forename: Alasdair G
authors.initials: AG
authors.lastname: Rooney
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh EH16 4UU, United Kingdom.
authors.forename: Charles
authors.initials: C
authors.lastname: Ffrench-Constant
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.|Center for Developmental Genetics and Department of Anesthesiology, Stony Brook University, Stony Brook, NY 11794.
authors.forename: Grigori
authors.initials: G
authors.lastname: Enikolopov
authors.affiliation: Department of Developmental Biology and Cancer Research, Faculty of Medicine, The Hebrew University, Jerusalem 91120, Israel; keshet@cc.huji.ac.il.
authors.forename: Eli
authors.initials: E
authors.lastname: Keshet
mesh_terms: D000375:Aging; D000818:Animals; D048430:Cell Shape; D002560:Cerebrovascular Circulation; D018891:Dentate Gyrus / Q000098:blood supply / Q000166:cytology* / Q000502:physiology; D005260:Female; D015870:Gene Expression; D008297:Male; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000502:physiology*; D055495:Neurogenesis; D055153:Stem Cell Niche; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse
keywords: VEGF; adult neurogenesis; aging; neural stem cells; neurovascular