The perivascular niche for neurogenesis was first reported as the co-association of newly generated neurons and their progenitors with both dividing and mitotically quiescent endothelial cells in restricted regions of the brain in adult birds and mammals alike. This review attempts to summarize our present understanding of the interaction of blood vessels with neural stem and progenitor cells, addressing both glial and neuronal progenitor cell interactions in the perivascular niche. We review the molecular interactions that are most critical to the endothelial control of stem and progenitor cell mobilization and differentiation. The focus throughout will be on defining those perivascular ligand-receptor interactions shared among these systems, as well as those that clearly differ as a function of cell type and setting, by which specificity may be achieved in the development of targeted therapeutics.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Critical steps to tumor metastasis: alterations of tumor microenvironment and extracellular matrix in the formation of pre-metastatic and metastatic niche
Cell & Bioscience Open Access 28 July 2020
Nature Communications Open Access 30 October 2018
Human neural stem cell-induced endothelial morphogenesis requires autocrine/paracrine and juxtacrine signaling
Scientific Reports Open Access 04 July 2016
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Goldman, S.A. Adult neurogenesis: From canaries to the clinic. J. Neurobiol. 36, 267–286 (1998).
Gage, F.H. Mammalian neural stem cells. Science 287, 1433–1438 (2000).
Alvarez-Buylla, A., Garcia-Verdugo, J.M. & Tramontin, A. A unified hypothesis on the lineage of neural stem cells. Nat. Rev. Neurosci. 2, 287–293 (2001).
Morshead, C.M. et al. Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron 13, 1071–1082 (1994).
Sanai, N. et al. Unique astrocyte ribbon in adult human brain contains neural stem cells, but lacks chain migration. Nature 427, 740–744 (2004).
Luskin, M.B. Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron 11, 173–189 (1993).
Lois, C. & Alvarez-Buylla, A. Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc. Natl. Acad. Sci. USA 90, 2074–2077 (1993).
Kirschenbaum, B. et al. In vitro neuronal production and differentiation by precursor cells derived from the adult human forebrain. Cereb. Cortex 4, 576–589 (1994).
Pincus, D.W. et al. Fibroblast growth factor-2/brain-derived neurotrophic factor–associated maturation of new neurons generated from adult human subependymal cells. Ann. Neurol. 43, 576–585 (1998).
Eriksson, P.S. et al. Neurogenesis in the adult human hippocampus. Nat. Med. 4, 1313–1317 (1998).
Roy, N.S. et al. In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus. Nat. Med. 6, 271–277 (2000).
Ming, G.L. & Song, H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70, 687–702 (2011).
Nishiyama, A., Komitova, M., Suzuki, R. & Zhu, X. Polydendrocytes (NG2 cells): multifunctional cells with lineage plasticity. Nat. Rev. Neurosci. 10, 9–22 (2009).
Goldman, S.A. Stem and progenitor cell–based therapy of the human central nervous system. Nat. Biotechnol. 23, 862–871 (2005).
Potten, C.S. & Loeffler, M. Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development 110, 1001–1020 (1990).
Doetsch, F., Petreanu, L., Caille, I., Garcia-Verdugo, J.M. & Alvarez-Buylla, A. EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36, 1021–1034 (2002).
Kronenberg, G. et al. Subpopulations of proliferating cells of the adult hippocampus respond differently to physiologic neurogenic stimuli. J. Comp. Neurol. 467, 455–463 (2003).
Nunes, M.C. et al. Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain. Nat. Med. 9, 439–447 (2003).
Ihrie, R.A. & Alvarez-Buylla, A. Lake-front property: a unique germinal niche by the lateral ventricles of the adult brain. Neuron 70, 674–686 (2011).
Shen, Q. et al. Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell 3, 289–300 (2008).
Tavazoie, M. et al. A specialized vascular niche for adult neural stem cells. Cell Stem Cell 3, 279–288 (2008).
Palmer, T.D., Willhoite, A.R. & Gage, F.H. Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 425, 479–494 (2000).
Louissaint, A. Jr., Rao, S., Leventhal, C. & Goldman, S.A. Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron 34, 945–960 (2002).
Leventhal, C., Rafii, S., Rafii, D., Shahar, A. & Goldman, S.A. Endothelial trophic support of neuronal production and recruitment from the adult mammalian subependyma. Mol. Cell. Neurosci. 13, 450–464 (1999).
Ohab, J.J., Fleming, S., Blesch, A. & Carmichael, S. A neurovascular niche for neurogenesis after stroke. J. Neurosci. 26, 13007–13016 (2006).
Bovetti, S. et al. Blood vessels form a scaffold for neuroblast migration in the adult olfactory bulb. J. Neurosci. 27, 5976–5980 (2007).
Snapyan, M. et al. Vasculature guides migrating neuronal precursors in the adult mammalian forebrain via brain-derived neurotrophic factor signaling. J. Neurosci. 29, 4172–4188 (2009).
Shen, Q. et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304, 1338–1340 (2004).
Goldman, S.A. & Nottebohm, F. Neuronal production, migration and differentiation in a vocal control nucleus of the adult female canary brain. Proc. Natl. Acad. Sci. USA 80, 2390–2394 (1983).
Cleaver, O. & Melton, D. Endothelial signaling during development. Nat. Med. 9, 661–668 (2003).
Calabrese, C. et al. A perivascular niche for brain tumor stem cells. Cancer Cell 11, 69–82 (2007).
Cao, L. et al. VEGF links hippocampal activity with neurogenesis, learning and memory. Nat. Genet. 36, 827–835 (2004).
Schänzer, A. et al. Direct stimulation of adult neural stem cells in vitro and neurogenesis in vivo by vascular endothelial growth factor. Brain Pathol. 14, 237–248 (2004).
Licht, T. et al. Reversible modulations of neuronal plasticity by VEGF. Proc. Natl. Acad. Sci. USA 108, 5081–5086 (2011).
Wurmser, A.E. et al. Cell fusion–independent differentiation of neural stem cells to the endothelial lineage. Nature 430, 350–356 (2004).
Wang, R. et al. Glioblastoma stem-like cells give rise to tumor endothelium. Nature 468, 829–833 (2010).
Lin, J.H. et al. Purinergic signaling regulates neural progenitor cell expansion and neurogenesis. Dev. Biol. 302, 356–366 (2007).
Braun, N. et al. Expression of the ecto-ATPase NTPDase2 in the germinal zones of the developing and adult rat brain. Eur. J. Neurosci. 17, 1355–1364 (2003).
Agresti, C. et al. Metabotropic P2 receptor activation regulates oligodendrocyte progenitor migration and development. Glia 50, 132–144 (2005).
Burnstock, G. Historical review: ATP as a neurotransmitter. Trends Pharmacol. Sci. 27, 166–176 (2006).
Packer, M.A. et al. Nitric oxide negatively regulates mammalian adult neurogenesis. Proc. Natl. Acad. Sci. USA 100, 9566–9571 (2003).
Chen, J. et al. Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice. J. Neurosci. 25, 2366–2375 (2005).
Park, C. et al. Inhibition of neuronal nitric oxide synthase enhances cell proliferation in the dentate gyrus of the adrenalectomized rat. Neurosci. Lett. 309, 9–12 (2001).
Cheng, A., Wang, S., Cai, J., Rao, M.S. & Mattson, M.P. Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain. Dev. Biol. 258, 319–333 (2003).
Moreno-López, B. et al. Nitric oxide is a physiological inhibitor of neurogenesis in the adult mouse subventricular zone and olfactory bulb. J. Neurosci. 24, 85–95 (2004).
Torroglosa, A. et al. Nitric oxide decreases subventricular zone stem cell proliferation by inhibition of epidermal growth factor receptor and phosphoinositide-3-kinase/Akt pathway. Stem Cells 25, 88–97 (2007).
Li, Q., Ford, M.C., Lavik, E.B. & Madri, J.A. Modeling the neurovascular niche: VEGF- and BDNF-mediated cross-talk between neural stem cells and endothelial cells: an in vitro study. J. Neurosci. Res. 84, 1656–1668 (2006).
Murillo-Carretero, M., Torroglosa, A., Castro, C., Villalobo, A. & Estrada, C. S-nitrosylation of the epidermal growth factor receptor: a regulatory mechanism of receptor tyrosine kinase activity. Free Radic. Biol. Med. 46, 471–479 (2009).
Reif, A. et al. Differential effect of endothelial nitric oxide synthase (NOS-III) on the regulation of adult neurogenesis and behavior. Eur. J. Neurosci. 20, 885–895 (2004).
Zhu, D.Y., Liu, S.H., Sun, H.S. & Lu, Y.M. Expression of inducible nitric oxide synthase after focal cerebral ischemia stimulates neurogenesis in the adult rodent dentate gyrus. J. Neurosci. 23, 223–229 (2003).
Carreira, B.P. et al. Nitric oxide stimulates the proliferation of neural stem cells bypassing the epidermal growth factor receptor. Stem Cells 28, 1219–1230 (2010).
Luo, C.X. et al. Bidirectional regulation of neurogenesis by neuronal nitric oxide synthase derived from neurons and neural stem cells. Stem Cells 28, 2041–2052 (2010).
Charles, N. et al. Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells. Cell Stem Cell 6, 141–152 (2010).
Eyler, C.E. et al. Glioma stem cell proliferation and tumor growth are promoted by nitric oxide synthase-2. Cell 146, 53–66 (2011).
Dawson, D.W. et al. Pigment epithelium–derived factor: a potent inhibitor of angiogenesis. Science 285, 245–248 (1999).
Ramírez-Castillejo, C. et al. Pigment epithelium–derived factor is a niche signal for neural stem cell renewal. Nat. Neurosci. 9, 331–339 (2006).
Andreu-Agulló, C., Morante-Redolat, J.M., Delgado, A.C. & Farinas, I. Vascular niche factor PEDF modulates Notch-dependent stemness in the adult subependymal zone. Nat. Neurosci. 12, 1514–1523 (2009).
Ables, J.L., Breunig, J., Eisch, A.J. & Rakic, P. Not(ch) just development: Notch signaling in the adult brain. Nat. Rev. Neurosci. 12, 269–283 (2011).
Noguera-Troise, I. et al. Blockade of Dll4 inhibits tumor growth by promoting non-productive angiogenesis. Nature 444, 1032–1037 (2006).
Ridgway, J. et al. Inhibition of Dll4 signaling inhibits tumor growth by deregulating angiogenesis. Nature 444, 1083–1087 (2006).
Klein, R., Conway, D., Parada, L.F. & Barbacid, M. The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain. Cell 61, 647–656 (1990).
Young, K.M., Merson, T.D., Sotthibundhu, A., Coulson, E.J. & Bartlett, P.F. p75 neurotrophin receptor expression defines a population of BDNF-responsive neurogenic precursor cells. J. Neurosci. 27, 5146–5155 (2007).
Galvão, R.P., Garcia-Verdugo, J.M. & Alvarez-Buylla, A. Brain-derived neurotrophic factor signaling does not stimulate subventricular zone neurogenesis in adult mice and rats. J. Neurosci. 28, 13368–13383 (2008).
Chiaramello, S. et al. BDNF/TrkB interaction regulates migration of SVZ precursor cells via PI3-K and MAP-K signaling pathways. Eur. J. Neurosci. 26, 1780–1790 (2007).
Donovan, M.H., Yamaguchi, M. & Eisch, A.J. Dynamic expression of TrkB receptor protein on proliferating and maturing cells in the adult mouse dentate gyrus. Hippocampus 18, 435–439 (2008).
Ahmed, S., Reynolds, B.A. & Weiss, S. BDNF enhances the differentiation, but not the survival, of CNS stem cell–derived neuronal precursors. J. Neurosci. 15, 5765–5778 (1995).
Kirschenbaum, B. & Goldman, S.A. Brain-derived neurotrophic factor promotes the survival of neurons arising from the adult rat forebrain subependymal zone. Proc. Natl. Acad. Sci. USA 92, 210–214 (1995).
Emsley, J.G. & Hagg, T. a6b1 integrin directs migration of neuronal precursors in adult mouse forebrain. Exp. Neurol. 183, 273–285 (2003).
Whitman, M.C., Fan, W., Rela, L., Rodriguez-Gil, D.J. & Greer, C.A. Blood vessels form a migratory scaffold in the rostral migratory stream. J. Comp. Neurol. 516, 94–104 (2009).
Kokovay, E. et al. Adult SVZ lineage cells home to and leave the vascular niche via differential responses to SDF1/CXCR4 signaling. Cell Stem Cell 7, 163–173 (2010).
Lim, D.A. et al. Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron 28, 713–726 (2000).
Mirzadeh, Z., Merkle, F.T., Soriano-Navarro, M., Garcia-Verdugo, J.M. & Alvarez-Buylla, A. Neural stem cells confer unique pinwheel architecture to the ventricular surface in neurogenic regions of the adult brain. Cell Stem Cell 3, 265–278 (2008).
Han, Y.G. et al. Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nat. Neurosci. 11, 277–284 (2008).
Lehtinen, M.K. et al. The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron 69, 893–905 (2011).
Doetsch, F., Garcia-Verdugo, J.M. & Alvarez-Buylla, A. Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J. Neurosci. 17, 5046–5061 (1997).
Quiñones-Hinojosa, A. et al. Cellular composition and cytoarchitecture of the adult human subventricular zone: a niche of neural stem cells. J. Comp. Neurol. 494, 415–434 (2006).
Rasika, S., Alvarez-Buylla, A. & Nottebohm, F. BDNF mediates the effects of testosterone on the survival of new neurons in an adult brain. Neuron 22, 53–62 (1999).
Hartog, T.E. et al. Brain-derived neurotrophic factor signaling in the HVC is required for testosterone-induced song of female canaries. J. Neurosci. 29, 15511–15519 (2009).
Bergers, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell Biol. 2, 737–744 (2000).
Kim, D.H. et al. Testosterone-induced matrix metalloproteinase activation is a checkpoint for neuronal addition to the adult songbird brain. J. Neurosci. 28, 208–216 (2008).
Wang, L. et al. Matrix metalloproteinase 2 (MMP2) and MMP9 secreted by erythropoietin-activated endothelial cells promote neural progenitor cell migration. J. Neurosci. 26, 5996–6003 (2006).
Jin, K. et al. Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc. Natl. Acad. Sci. USA 98, 4710–4715 (2001).
Arvidsson, A., Collin, T., Kirik, D., Kokaia, Z. & Lindvall, O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat. Med. 8, 963–970 (2002).
Parent, J.M., Vexler, Z.S., Gong, C., Derugin, N. & Ferriero, D.M. Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann. Neurol. 52, 802–813 (2002).
Yamashita, T. et al. Subventricular zone–derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum. J. Neurosci. 26, 6627–6636 (2006).
Chmielnicki, E., Benraiss, A., Economides, A.N. & Goldman, S.A. Adenovirally expressed noggin and brain-derived neurotrophic factor cooperate to induce new medium spiny neurons from resident progenitor cells in the adult striatal ventricular zone. J. Neurosci. 24, 2133–2142 (2004).
Wang, X. et al. P2X7 receptor inhibition improves recovery after spinal cord injury. Nat. Med. 10, 821–827 (2004).
Greenberg, D.A. & Jin, K. From angiogenesis to neuropathology. Nature 438, 954–959 (2005).
Monje, M.L. & Palmer, T. Radiation injury and neurogenesis. Curr. Opin. Neurol. 16, 129–134 (2003).
Monje, M.L., Toda, H. & Palmer, T. Inflammatory blockade restores adult hippocampal neurogenesis. Science 302, 1760–1765 (2003).
Sim, F.J. et al. Complementary patterns of gene expression by adult human oligodendrocyte progenitor cells and their white matter environment. Ann. Neurol. 59, 763–779 (2006).
Poimenidi, E., Hatziapostolou, M. & Papadimitriou, E. Serum stimulates Pleiotrophin gene expression in an AP-1–dependent manner in human endothelial and glioblastoma cells. Anticancer Res. 29, 349–354 (2009).
Chang, Y. et al. Secretion of pleiotrophin stimulates breast cancer progression through remodeling of the tumor microenvironment. Proc. Natl. Acad. Sci. USA 104, 10888–10893 (2007).
Arai, K. & Lo, E.H. An oligovascular niche: cerebral endothelial cells promote the survival and proliferation of oligodendrocyte precursor cells. J. Neurosci. 29, 4351–4355 (2009).
Gadea, A., Aguirre, A., Haydar, T.F. & Gallo, V. Endothelin-1 regulates oligodendrocyte development. J. Neurosci. 29, 10047–10062 (2009).
Aerts, I. et al. The expression of ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (E-NPP1) is correlated with astrocytic tumor grade. Clin. Neurol. Neurosurg. 113, 224–229 (2011).
Bao, S. et al. Stem cell–like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 66, 7843–7848 (2006).
Gilbertson, R.J. & Rich, J.N. Making a tumor's bed: glioblastoma stem cells and the vascular niche. Nat. Rev. Cancer 7, 733–736 (2007).
Cho, S.R. et al. Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease. J. Clin. Invest. 117, 2889–2902 (2007).
Im, S.H. et al. Induction of striatal neurogenesis enhances functional recovery in an adult animal model of neonatal hypoxic-ischemic brain injury. Neuroscience 169, 259–268 (2010).
We thank M. Nedergaard for her comments on the manuscript and A. Benraiss and C. McClain for designing the schematics. Work discussed in the Goldman laboratory was supported by the National Institute of Neurological Disorders and Stroke (grants R37NS29813, R01NS75345 and R01NS39559) and by grants from the National Multiple Sclerosis Society, the G. Harold and Leila Y. Mathers Charitable Foundation, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the CHDI Foundation, and the New York State Stem Cell Research Program.
The authors declare no competing financial interests.
About this article
Cite this article
Goldman, S., Chen, Z. Perivascular instruction of cell genesis and fate in the adult brain. Nat Neurosci 14, 1382–1389 (2011). https://doi.org/10.1038/nn.2963
Critical steps to tumor metastasis: alterations of tumor microenvironment and extracellular matrix in the formation of pre-metastatic and metastatic niche
Cell & Bioscience (2020)
Nature Neuroscience (2020)
Nature Communications (2018)
Brain Structure and Function (2018)
Nature Medicine (2016)