Current Stem Cell Reports

, Volume 4, Issue 1, pp 33–38 | Cite as

The Paracrine Neural Stem Cell Niche: New Actors in the Play

  • María-Victoria Gómez-Gaviro
  • Manuel Desco
Stem Cell Switches and Regulators (KK Hirschi, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Stem Cell Switches and Regulators


Purpose of Review

The neural stem cell (NSC) niche has been partially characterized and defined in the mammalian brain. Two adult niches have been identified: the dentate gyrus (DG) in the hippocampus and the subventricular zone (SVZ). Neural stem cells reside in these microenvironments near to vascular cells, with which they communicate through paracrine factors. This review summarizes the latest vascular paracrine factors identified to play a role in the NSC niche. Soluble factors released by the vasculature, such as pigment epithelium-derived factor (PEDF), platelet-derived growth factor (PDGF), betacellulin (BTC), vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), neurotropin (NT)-3, and Notch ligand Jagged 1, regulate NSC behavior in the niche.

Recent Findings

New paracrine factors, like APP and EGFL-7, have been recently identified as part of the NSC niche. The choroid plexus of the lateral ventricle (LVCP) has also been identified as a key regulator of the NSC niche. Finally, exosomes containing proteins or microRNAs are released by different cell types in the NSC niche and are considered to play a role in the regulation of NSCs.


The niche vasculature and the choroid plexus are key components of the NSC niche that determine NSC fate by releasing paracrine factors, either directly or contained in exosomes. Understanding the complexity of the microenvironment and NSC niche cytoarchitecture will help to unveil the regulatory mechanisms that control NSC biology.


Vasculature Soluble factor Neural stem cell niche Endothelium 



The CNIC is supported by the Ministry of Economy, Industry and Competitiveness (MEIC) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). This study was supported by BRADE S2013/ICE-2958 (Comunidad de Madrid), Cardiovascular Research Network (RIC, RD12/0042/0057) from the Spanish Ministerio de Economía y Competitividad, Fondos FEDER “Una manera de hacer Europa” and CIBERSAM Centro de Investigación Biomédica en Red de Salud Mental.

Compliance with Ethical Standards

Conflict of Interest

Maria Victoria Gómez-Gaviro and Manuel Desco declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci U S A. 2002;99(18):11946–50. Scholar
  2. 2.
    • Gómez-Gaviro MV, Lovell-Badge R, Fernández-Avilés F, Lara-Pezzi E. The vascular stem cell niche. J Cardiovasc Transl Res. 2012;5(5):618–30. Up to date review of the role of the vasculature on different stem cell niches. CrossRefPubMedGoogle Scholar
  3. 3.
    Lee JE. Basic helix-loop-helix genes in neural development. Curr Opin Neurobiol. 1997;7(1):13–20. Scholar
  4. 4.
    Ottone C, Krusche B, Whitby A, Clements M, Quadrato G, Pitulescu ME, et al. Direct cell-cell contact with the vascular niche maintains quiescent neural stem cells. Nat Cell Biol. 2014;16(11):1045–56, Scholar
  5. 5.
    Shen Q, Goderie SK, Jin L, Karanth N, Sun Y, Abramova N, et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science. 2004;304(5675):1338–40. Scholar
  6. 6.
    • Gómez-Gaviro MV, Scott CE, Sesay AK, Matheu A, Booth S, Galichet C, et al. Betacellulin promotes cell proliferation in the neural stem cell niche and stimulates neurogenesis. Proc Natl Acad Sci U S A. 2012;109(4):1317–22. This study shows that BTC is secreted by endothelial cells and promotes neurogenesis in vitro and in vivo. CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Chou C-H, Sinden JD, Couraud P-O, Modo M. In vitro modeling of the neurovascular environment by coculturing adult human brain endothelial cells with human neural stem cells. PLoS One. 2014;9(9):e106346. Scholar
  8. 8.
    Ramírez-Castillejo C, Sánchez-Sánchez F, Andreu-Agulló C, Ferrón SR, Aroca-Aguilar JD, Sánchez P, et al. Pigment epithelium–derived factor is a niche signal for neural stem cell renewal. Nat Neurosci. 2006;9(3):331–9. Scholar
  9. 9.
    Andreu-Agulló C, Morante-Redolat JM, Delgado AC, Fariñas I. Vascular niche factor PEDF modulates notch-dependent stemness in the adult subependymal zone. Nat Neurosci. 2009;12(12):1514–23. Scholar
  10. 10.
    Jackson EL, Garcia-Verdugo JM, Gil-Perotin S, Roy M, Quinones-Hinojosa A, VandenBerg S, et al. PDGFRα-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron. 2006;51(2):187–99. Scholar
  11. 11.
    Bath KG, Akins MR, Lee FS. BDNF control of adult SVZ neurogenesis. Dev Psychobiol. 2012;54(6):578–89. Scholar
  12. 12.
    Leventhal C, Rafii S, Rafii D, Shahar A, Goldman SA. Endothelial trophic support of neuronal production and recruitment from the adult mammalian subependyma. Mol Cell Neurosci. 1999;13(6):450–64. Scholar
  13. 13.
    Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu X-F, Breitman ML, et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 1995;376(6535):62–6. Scholar
  14. 14.
    Shalaby F, Ho J, Stanford WL, Fischer K-D, Schuh AC, Schwartz L, et al. A requirement for Flk1 in primitive and definitive hematopoiesis and vasculogenesis. Cell. 89(6):981–90.
  15. 15.
    Masatsugu Ema PF, Zhang WJ, Hirashima M, Reid T, Stanford WL, Orkin S, et al. Combinatorial effects of Flk1 and Tal1 on vascular and hematopoietic development in the mouse. Genes Dev. 2003;17:380–93.CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Wada T, Haigh JJ, Ema M, Hitoshi S, Chaddah R, Rossant J, et al. Vascular endothelial growth factor directly inhibits primitive neural stem cell survival but promotes definitive neural stem cell survival. J Neurosci. 2006;26(25):6803–12. Scholar
  17. 17.
    Yoshihito Miki NN, Ikeda N, Coffin RS, Kuroiwa T, Miyatake S-I. Vascular endothelial growth factor gene-transferred bone marrow stromal cells engineered with a herpes simplex virus type 1 vector can improve neurological deficits and reduce infarction volume in rat brain ischemia. Neurosurgery. 2007;61(3):586–95. Scholar
  18. 18.
    Li S-F, Sun Y-B, Meng Q-H, Li S-R, Yao W-C, Hu G-J, et al. Recombinant adeno-associated virus serotype 1-vascular endothelial growth factor promotes neurogenesis and neuromigration in the subventricular zone and rescues neuronal function in ischemic rats. Neurosurgery. 2009;65(4):771–9. Scholar
  19. 19.
    Delgado Ana C, Ferrón Sacri R, Vicente D, Porlan E, Perez-Villalba A, Trujillo Carmen M, et al. Endothelial NT-3 delivered by vasculature and CSF promotes quiescence of subependymal neural stem cells through nitric oxide induction. Neuron. 83(3):572–85.
  20. 20.
    Bath KG, Lee FS. Neurotrophic factor control of adult SVZ neurogenesis. Developmental Neurobiology. 2010;70(5):339–49. Scholar
  21. 21.
    Shimazu K, Zhao M, Sakata K, Akbarian S, Bates B, Jaenisch R, et al. NT-3 facilitates hippocampal plasticity and learning and memory by regulating neurogenesis. Learn Mem. 2006;13(3):307–15. Scholar
  22. 22.
    Gaviro MVG, Fernández PLS, Badge RL, Avilés FF. Looking for the niche: substance delivery into the lateral ventricle of the brain: the osmotic minipump system. In: Turksen K, editor. Stem cell niche: methods and protocols. Totowa: Humana Press; 2013. p. 135–40. Scholar
  23. 23.
    Tombran-Tink J, Barnstable CJ. PEDF: a multifaceted neurotrophic factor. Nat Rev Neurosci. 2003;4(8):628–36. Scholar
  24. 24.
    Zhu C, Zhang X, Qiao H, Wang L, Zhang X, Xing Y, et al. The intrinsic PEDF is regulated by PPARγ in permanent focal cerebral ischemia of rat. Neurochem Res. 2012;37(10):2099–107. Scholar
  25. 25.
    Koichi A, Tetsuro A, Masahiro K, Kuniyuki N, Koji I, Junya K, et al. PDGF receptor β signaling in pericytes following ischemic brain injury. Curr Neurovasc Res. 2012;9(1):1–9. Scholar
  26. 26.
    Mirzadeh Z, Merkle FT, Soriano-Navarro M, Garcia-Verdugo JM, Alvarez-Buylla A. Neural stem cells confer unique pinwheel architecture to the ventricular surface in neurogenic regions of the adult brain. Cell Stem Cell. 2008;3(3):265–78. Scholar
  27. 27.
    •• Sato Y, Uchida Y, Hu J, Young-Pearse TL, Niikura T, Mukouyama Y-S. Soluble APP functions as a vascular niche signal that controls adult neural stem cell number. Development. 2017;144(15):2730–6. This study demonstrates that soluble APP is a vascular niche signal that negatively regulates NSCs growth in culture. CrossRefPubMedGoogle Scholar
  28. 28.
    •• Bicker F, Vasic V, Horta G, Ortega F, Nolte H, Kavyanifar A, et al. Neurovascular EGFL7 regulates adult neurogenesis in the subventricular zone and thereby affects olfactory perception. Nat Commun. 2017;8:15922. This study shows that EGFL-7 is secreted by endothelial cells and NSCs promoting NSCs quiescence and neural progenitor cells differentiation. CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Jolivel V, Bicker F, Binamé F, Ploen R, Keller S, Gollan R, et al. Perivascular microglia promote blood vessel disintegration in the ischemic penumbra. Acta Neuropathol. 2015;129(2):279–95. Scholar
  30. 30.
    Nikolić I, Stanković ND, Bicker F, Meister J, Braun H, Awwad K, et al. EGFL7 ligates α<sub>v</sub>β<sub>3</sub> integrin to enhance vessel formation. Blood. 2013;121(15):3041–50. Scholar
  31. 31.
    Schmidt MHH, Bicker F, Nikolic I, Meister J, Babuke T, Picuric S, et al. Epidermal growth factor-like domain 7 (EGFL7) modulates notch signalling and affects neural stem cell renewal. Nat Cell Biol. 2009;11(7):873–80. Scholar
  32. 32.
    Redzic ZB, Preston JE, Duncan JA, Chodobski A, Szmydynger-Chodobska J. The choroid plexus-cerebrospinal fluid system: from development to aging. Current topics in developmental biology. Cambridge: Academic Press; 2005. p. 1–52.Google Scholar
  33. 33.
    •• Silva-Vargas V, Maldonado-Soto Angel R, Mizrak D, Codega P, Doetsch F. Age-dependent niche signals from the choroid plexus regulate adult neural stem cells. Cell Stem Cell. 19(5):643–52. This study shows that choroid plexus of the lateral ventricles secretes factors that promotes proliferation of NSCs and neural progenitor cells.
  34. 34.
    Baird GS, Nelson SK, Keeney TR, Stewart A, Williams S, Kraemer S, et al. Age-dependent changes in the cerebrospinal fluid proteome by slow off-rate modified aptamer array. Am J Pathol. 180(2):446–56.
  35. 35.
    Bartke A, Sun LY, Longo V. Somatotropic signaling: trade-offs between growth, reproductive development, and longevity. Physiol Rev. 2013;93(2):571–98. Scholar
  36. 36.
    Sawamoto K, Wichterle H, Gonzalez-Perez O, Cholfin JA, Yamada M, Spassky N, et al. New neurons follow the flow of cerebrospinal fluid in the adult brain. Science. 2006;311(5761):629–32. Scholar
  37. 37.
    •• Bátiz LF, Castro MA, Burgos PV, Velásquez ZD, Muñoz RI, Lafourcade CA, et al. Exosomes as novel regulators of adult neurogenic niches. Front Cell Neurosci. 2015;9:501. Up to date review of the potencial role of exosomes of adult neurogenesis. PubMedGoogle Scholar
  38. 38.
    Graner MW, Alzate O, Dechkovskaia AM, Keene JD, Sampson JH, Mitchell DA, et al. Proteomic and immunologic analyses of brain tumor exosomes. FASEB J. 2009;23(5):1541–57. Scholar
  39. 39.
    Nazarenko I, Rana S, Baumann A, McAlear J, Hellwig A, Trendelenburg M, et al. Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer Res. 2010;70(4):1668–78. Scholar
  40. 40.
    Lai RC, Chen TS, Lim SK. Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease. Regen Med. 2011;6(4):481–92. Scholar
  41. 41.
    Hajrasouliha AR, Jiang G, Lu Q, Lu H, Kaplan HJ, Zhang H-G, et al. Exosomes from retinal astrocytes contain antiangiogenic components that inhibit laser-induced choroidal neovascularization. J Biol Chem. 2013;288(39):28058–67. Scholar
  42. 42.
    Wendler F, Bota-Rabassedas N, Franch-Marro X. Cancer becomes wasteful: emerging roles of exosomes(†) in cell-fate determination. J Extracell Vesicles. 2013;2.
  43. 43.
    Dumont CM, Piselli JM, Kazi N, Bowman E, Li G, Linhardt RJ, et al. Factors released from endothelial cells exposed to flow impact adhesion, proliferation, and fate choice in the adult neural stem cell lineage. Stem Cells Dev. 2017;26(16):1199–213. Scholar
  44. 44.
    Kole R, Krainer AR, Altman S. RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nat Rev Drug Discov. 2012;11(2):125–40. Scholar
  45. 45.
    Rogalska ME, Tajnik M, Licastro D, Bussani E, Camparini L, Mattioli C, et al. Therapeutic activity of modified U1 core spliceosomal particles. Nat Commun. 2016;7:11168. Scholar
  46. 46.
    Naryshkin NA, Weetall M, Dakka A, Narasimhan J, Zhao X, Feng Z, et al. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science. 2014;345(6197):688–93. Scholar
  47. 47.
    Palacino J, Swalley SE, Song C, Cheung AK, Shu L, Zhang X, et al. SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice. Nat Chem Biol. 2015;11(7):511–7. CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • María-Victoria Gómez-Gaviro
    • 1
    • 2
    • 3
  • Manuel Desco
    • 1
    • 2
    • 3
    • 4
  1. 1.Instituto de Investigación Sanitaria Gregorio MarañónMadridSpain
  2. 2.Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)MadridSpain
  3. 3.Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)MadridSpain
  4. 4.Departamento de Bioingeniería e Ingeniería AeroespacialUniversidad Carlos III de MadridMadridSpain

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