Skip to main content
Log in

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

  • Stem Cell Switches and Regulators (KK Hirschi, Section Editor)
  • Published:
Current Stem Cell Reports Aims and scope Submit manuscript

Abstract

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.

Summary

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

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

  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. https://doi.org/10.1073/pnas.182296499.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s12265-012-9371-x. Up to date review of the role of the vasculature on different stem cell niches.

    Article  PubMed  Google Scholar 

  3. Lee JE. Basic helix-loop-helix genes in neural development. Curr Opin Neurobiol. 1997;7(1):13–20. https://doi.org/10.1016/S0959-4388(97)80115-8.

    Article  PubMed  Google Scholar 

  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, https://www.nature.com/articles/ncb3045#supplementary-information. https://doi.org/10.1038/ncb3045.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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. https://doi.org/10.1126/science.1095505.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1073/pnas.1016199109. This study shows that BTC is secreted by endothelial cells and promotes neurogenesis in vitro and in vivo.

    Article  PubMed Central  PubMed  Google Scholar 

  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. https://doi.org/10.1371/journal.pone.0106346.

    Article  PubMed Central  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nn1657.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nn.2437 https://www.nature.com/articles/nn.2437#supplementary-information.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.neuron.2006.06.012.

    Article  CAS  PubMed  Google Scholar 

  11. Bath KG, Akins MR, Lee FS. BDNF control of adult SVZ neurogenesis. Dev Psychobiol. 2012;54(6):578–89. https://doi.org/10.1002/dev.20546.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1006/mcne.1999.0762.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/376062a0.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/s0092-8674(00)80283-4.

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  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. https://doi.org/10.1523/jneurosci.0526-06.2006.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1227/01.NEU.0000290907.30814.42.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1227/01.neu.0000349931.61771.52.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.neuron.2014.06.015.

  20. Bath KG, Lee FS. Neurotrophic factor control of adult SVZ neurogenesis. Developmental Neurobiology. 2010;70(5):339–49. https://doi.org/10.1002/dneu.20781.

    CAS  PubMed Central  PubMed  Google Scholar 

  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. https://doi.org/10.1101/lm.76006.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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. https://doi.org/10.1007/978-1-62703-508-8_11.

    Chapter  Google Scholar 

  23. Tombran-Tink J, Barnstable CJ. PEDF: a multifaceted neurotrophic factor. Nat Rev Neurosci. 2003;4(8):628–36. https://doi.org/10.1038/nrn1176.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s11064-012-0831-0.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.2174/156720212799297100.

    Article  Google Scholar 

  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. https://doi.org/10.1016/j.stem.2008.07.004.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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. https://doi.org/10.1242/dev.143370. This study demonstrates that soluble APP is a vascular niche signal that negatively regulates NSCs growth in culture.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/ncomms15922. This study shows that EGFL-7 is secreted by endothelial cells and NSCs promoting NSCs quiescence and neural progenitor cells differentiation.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s00401-014-1372-1.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1182/blood-2011-11-394882.

    Article  PubMed  Google Scholar 

  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. http://www.nature.com/ncb/journal/v11/n7/suppinfo/ncb1896_S1.html. https://doi.org/10.1038/ncb1896.

    Article  CAS  PubMed  Google Scholar 

  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. •• 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. https://doi.org/10.1016/j.stem.2016.06.013. This study shows that choroid plexus of the lateral ventricles secretes factors that promotes proliferation of NSCs and neural progenitor cells.

  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. https://doi.org/10.1016/j.ajpath.2011.10.024.

  35. Bartke A, Sun LY, Longo V. Somatotropic signaling: trade-offs between growth, reproductive development, and longevity. Physiol Rev. 2013;93(2):571–98. https://doi.org/10.1152/physrev.00006.2012.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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. https://doi.org/10.1126/science.1119133.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.3389/fncel.2015.00501. Up to date review of the potencial role of exosomes of adult neurogenesis.

    PubMed  Google Scholar 

  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. https://doi.org/10.1096/fj.08-122184.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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. https://doi.org/10.1158/0008-5472.can-09-2470.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.2217/rme.11.35.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1074/jbc.M113.470765.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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. https://doi.org/10.3402/jev.v2i0.22390.

  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. https://doi.org/10.1089/scd.2016.0350.

    Article  CAS  PubMed  Google Scholar 

  44. Kole R, Krainer AR, Altman S. RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nat Rev Drug Discov. 2012;11(2):125–40. https://doi.org/10.1038/nrd3625.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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. https://doi.org/10.1038/ncomms11168.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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. https://doi.org/10.1126/science.1250127.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nchembio.1837. http://www.nature.com/nchembio/journal/v11/n7/abs/nchembio.1837.html#supplementary-information

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to María-Victoria Gómez-Gaviro.

Ethics declarations

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.

Additional information

This article is part of the Topical Collection on Stem Cell Switches and Regulators

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gómez-Gaviro, MV., Desco, M. The Paracrine Neural Stem Cell Niche: New Actors in the Play. Curr Stem Cell Rep 4, 33–38 (2018). https://doi.org/10.1007/s40778-018-0112-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40778-018-0112-1

Keywords

Navigation