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Neural stem and progenitor cells support and protect adult hippocampal function via vascular endothelial growth factor secretion

Molecular Psychiatry volume 30, pages 2152–2167 (2025)Cite this article

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Abstract

Adult neural stem and progenitor cells (NSPCs) reside in the dentate gyrus (DG) of the hippocampus throughout the lifespan of most mammalian species. In addition to generating new neurons, NSPCs may alter their niche via secretion of growth factors and cytokines. We recently showed that adult DG NSPCs secrete vascular endothelial growth factor (VEGF), which is critical for maintaining adult neurogenesis. Here, we asked whether NSPC-derived VEGF alters hippocampal function independent of adult neurogenesis. We found that loss of NSPC-derived VEGF acutely impaired hippocampal memory, caused neuronal hyperexcitability and exacerbated excitotoxic injury. Conversely, we observed that overexpression of VEGF reduced microglial response to excitotoxic injury. We also found that NSPCs generate substantial proportions of total DG VEGF and VEGF disperses widely throughout the DG, both of which help explain how this anatomically-restricted cell population could modulate function broadly. These findings suggest that NSPCs actively support and protect DG function via secreted VEGF, thereby providing a non-neurogenic functional dimension to endogenous NSPCs.

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Fig. 1: NSPC-VEGF knockdown impairs hippocampal spatial memory.
Fig. 2: NSPC-VEGF knockdown increases DG excitability.
Fig. 3: VEGF disperses widely from a point source in the DG.
Fig. 4: NSPCs contribute VEGF to the DG in response to excitotoxic injury.
Fig. 5: NSPC-VEGF knockdown exacerbates acute excitotoxic injury.
Fig. 6: NSPC-VEGF knockdown exacerbation of excitotoxic injury persists 7 d later.
Fig. 7: Retroviral overexpression of VEGF protects against excitotoxic injury.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Charvet CJ, Finlay BL. Comparing adult hippocampal neurogenesis across species: translating time to predict the tempo in humans. Front Neurosci 2018;12:706.

    PubMed  PubMed Central  Google Scholar 

  2. Kempermann G, Gage FH, Aigner L, Song H, Curtis MA, Thuret S, et al. Human adult neurogenesis: evidence and remaining questions. Cell Stem Cell. 2018;23:25–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Willis CM, Nicaise AM, Peruzzotti-Jametti L, Pluchino S. The neural stem cell secretome and its role in brain repair. Brain Res. 2020;1729:146615.

    PubMed  Google Scholar 

  4. Li Y-D, Luo Y-J, Song J. Optimizing memory performance and emotional states: multi-level enhancement of adult hippocampal neurogenesis. Curr Opin Neurobiol. 2023;79:102693.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Choi SH, Tanzi RE. Adult neurogenesis in Alzheimer’s disease. Hippocampus. 2023;33:307–21.

    PubMed  Google Scholar 

  6. Mendes-Pinheiro B, Teixeira FG, Anjo SI, Manadas B, Behie LA, Salgado AJ. Secretome of undifferentiated neural progenitor cells induces histological and motor improvements in a rat model of Parkinson’s disease. Stem Cells Transl Med. 2018;7:829–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Tobin MK, Musaraca K, Disouky A, Shetti A, Bheri A, Honer WG, et al. Human hippocampal neurogenesis persists in aged adults and Alzheimer’s disease patients. Cell Stem Cell. 2019;24:974–82.e3.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Bacigaluppi M, Sferruzza G, Butti E, Ottoboni L, Martino G. Endogenous neural precursor cells in health and disease. Brain Res. 2020;1730:146619.

    CAS  PubMed  Google Scholar 

  9. de Almeida MMA, Goodkey K, Voronova, A. Regulation of microglia function by neural stem cells. Front Cell Neurosci. 2023;17:1130205.

  10. Tang C, Wang M, Wang P, Wang L, Wu Q, Guo W. Neural stem cells behave as a functional niche for the maturation of newborn neurons through the secretion of PTN. Neuron. 2019;101:32–44.e6.

    CAS  PubMed  Google Scholar 

  11. Zhou Y, Bond AM, Shade JE, Zhu Y, Davis CO, Wang X, et al. Autocrine Mfge8 signaling prevents developmental exhaustion of the adult neural stem cell pool. Cell Stem Cell. 2018;23:444–52.e4.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Butti E, Cattaneo S, Bacigaluppi M, Cambiaghi M, Scotti GM, Brambilla E, et al. Neural precursor cells tune striatal connectivity through the release of IGFBPL1. Nat Commun. 2022;13:7579.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kirby ED, Kuwahara AA, Messer RL, Wyss-Coray T. Adult hippocampal neural stem and progenitor cells regulate the neurogenic niche by secreting VEGF. PNAS. 2015;112:4128–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Lange C, Storkebaum E, de Almodóvar CR, Dewerchin M, Carmeliet P. Vascular endothelial growth factor: a neurovascular target in neurological diseases. Nat Rev Neurol. 2016;12:439–54.

    CAS  PubMed  Google Scholar 

  15. Shim JW, Madsen JR. VEGF signaling in neurological disorders. Int J Mol Sci. 2018;19:275.

    PubMed  PubMed Central  Google Scholar 

  16. Lagace DC, Whitman MC, Noonan MA, Ables JL, DeCarolis NA, Arguello AA, et al. Dynamic contribution of nestin-expressing stem cells to adult neurogenesis. J Neurosci 2007;27:12623–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Gerber HP, Hillan KJ, Ryan AM, Kowalski J, Keller GA, Rangell L, et al. VEGF is required for growth and survival in neonatal mice. Development. 1999;126:1149–59.

    CAS  PubMed  Google Scholar 

  18. Dause TJ, Kirby ED. Poor concordance of floxed sequence recombination in single neural stem cells: implications for cell autonomous studies. eNeuro 2020;7:ENEURO.0470–19.2020.

  19. Sun M-Y, Yetman MJ, Lee T-C, Chen Y, Jankowsky JL. Specificity and efficiency of reporter expression in adult neural progenitors vary substantially among nestin-CreERT2 lines. J Comp Neurol. 2014;522:1191–208.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Olpe C, Jessberger S. Cell population dynamics in the course of adult hippocampal neurogenesis: Remaining unknowns. Hippocampus. 2023;33:402–11.

    CAS  PubMed  Google Scholar 

  21. Rosso M, Wirz R, Loretan AV, Sutter NA, Pereira da Cunha CT, Jaric I, et al. Reliability of common mouse behavioural tests of anxiety: a systematic review and meta-analysis on the effects of anxiolytics. Neurosci Biobehav Rev. 2022:104928. https://doi.org/10.1016/j.neubiorev.2022.104928.

  22. Deyama S, Li X-Y, Duman RS. Neuron-specific deletion of VEGF or its receptor Flk-1 impairs recognition memory. Eur Neuropsychopharmacol. 2020;31:145–51.

    CAS  PubMed  Google Scholar 

  23. Cao L, Jiao X, Zuzga DS, Liu Y, Fong DM, Young D, et al. VEGF links hippocampal activity with neurogenesis, learning and memory. Nat Genet. 2004;36:827–35.

    CAS  PubMed  Google Scholar 

  24. Braganza O, Mueller-Komorowska D, Kelly T, Beck H. Quantitative properties of a feedback circuit predict frequency-dependent pattern separation. eLife. 2020;9:e53148.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Cayco-Gajic NA, Silver RA. Re-evaluating circuit mechanisms underlying pattern separation. Neuron. 2019;101:584–602.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Miller SM, Sahay A. Functions of adult-born neurons in hippocampal memory interference and indexing. Nat Neurosci 2019;22:1565–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. McHugh SB, Lopes-dos-Santos V, Gava GP, Hartwich K, Tam SKE, Bannerman DM, et al. Adult-born dentate granule cells promote hippocampal population sparsity. Nat Neurosci. 2022;25:1481–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Mac Gabhann F, Ji JW, Popel AS. Computational model of vascular endothelial growth factor spatial distribution in muscle and pro-angiogenic cell therapy. PLoS Comput Biol. 2006;2:e127.

  29. Serfling R, Lorenz C, Etzel M, Schicht G, Böttke T, Mörl M, et al. Designer tRNAs for efficient incorporation of non-canonical amino acids by the pyrrolysine system in mammalian cells. Nucleic Acids Res. 2018;46:1–10.

    CAS  PubMed  Google Scholar 

  30. Arsić A, Hagemann C, Stajković N, Schubert T, Nikić-Spiegel I. Minimal genetically encoded tags for fluorescent protein labeling in living neurons. Nat Commun. 2022;13:314.

    PubMed  PubMed Central  Google Scholar 

  31. Bessa-Neto D, Beliu G, Kuhlmann A, Pecoraro V, Doose S, Retailleau N, et al. Bioorthogonal labeling of transmembrane proteins with non-canonical amino acids unveils masked epitopes in live neurons. Nat Commun. 2021;12:6715.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Nikić I, Kang JH, Girona GE, Aramburu IV, Lemke EA. Labeling proteins on live mammalian cells using click chemistry. Nat Protoc. 2015;10:780–91.

    PubMed  Google Scholar 

  33. McCloskey DP, Croll SD, Scharfman HE. Depression of synaptic transmission by vascular endothelial growth factor in adult rat hippocampus and evidence for increased efficacy after chronic seizures. J Neurosci. 2005;25:8889–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Nicoletti JN, Lenzer J, Salerni EA, Shah SK, Elkady A, Khalid S, et al. Vascular endothelial growth factor attenuates status epilepticus-induced behavioral impairments in rats. Epilepsy Behav. 2010;19:272–7.

    PubMed  PubMed Central  Google Scholar 

  35. Cammalleri M, Martini D, Ristori C, Timperio AM, Bagnoli P. Vascular endothelial growth factor up-regulation in the mouse hippocampus and its role in the control of epileptiform activity. Eur J Neurosci. 2011;33:482–98.

    PubMed  Google Scholar 

  36. Bartsch T, Wulff P. The hippocampus in aging and disease: from plasticity to vulnerability. Neuroscience. 2015;309:1–16.

    CAS  PubMed  Google Scholar 

  37. Sloviter RS. Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science. 1987;235:73–6.

    CAS  PubMed  Google Scholar 

  38. Buckmaster PS, Jongen-Rêlo AL. Highly specific neuron loss preserves lateral inhibitory circuits in the dentate gyrus of kainate-induced epileptic rats. J Neurosci. 1999;19:9519–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Morin-Brureau M, Lebrun A, Rousset M, Fagni L, Bockaert J, de Bock F, et al. Epileptiform activity induces vascular remodeling and zonula occludens 1 downregulation in organotypic hippocampal cultures: role of VEGF signaling pathways. J Neurosci. 2011;31:10677–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Greene C, Hanley N, Reschke CR, Reddy A, Mäe MA, Connolly R, et al. Microvascular stabilization via blood-brain barrier regulation prevents seizure activity. Nat Commun. 2022;13:2003.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Willis CM, Nicaise AM, Hamel R, Pappa V, Peruzzotti-Jametti L, Pluchino S. Harnessing the Neural Stem Cell Secretome for Regenerative Neuroimmunology. Front Cell Neurosci 2020;14:590960.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Dause TJ, Denninger JK, Smith BM, Kirby ED. The neural stem cell secretome across neurodevelopment. Exp Neurol. 2022:114142. https://doi.org/10.1016/j.expneurol.2022.114142.

  43. Bracko O, Singer T, Aigner S, Knobloch M, Winner B, Ray J, et al. Gene expression profiling of neural stem cells and their neuronal progeny reveals IGF2 as a regulator of adult hippocampal neurogenesis. J Neurosci 2012;32:3376–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Williamson MR, Le SP, Franzen RL, Donlan NA, Rosow JL, Nicot-Cartsonis MS, et al. Subventricular zone cytogenesis provides trophic support for neural repair in a mouse model of stroke. Nat Commun. 2023;14:6341.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Croll SD, Goodman JH, Scharfman HE. Vascular endothelial growth factor (VEGF) in seizures: In: Binder DK, Scharfman HE, editors. Recent advances in epilepsy research. Springer US; 2004. p. 57–68. https://doi.org/10.1007/978-1-4757-6376-8_4.

  46. Licht TS, Keshet E. Delineating multiple functions of VEGF-A in the adult brain. Cell Mol Life Sci 2013;70:1727–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Egervari K, Potter G, Guzman-Hernandez ML, Salmon P, Soto-Ribeiro M, Kastberger B, et al. Astrocytes spatially restrict VEGF signaling by polarized secretion and incorporation of VEGF into the actively assembling extracellular matrix: secretion and function of VEGF in astrocytes. Glia. 2016;64:440–56.

    PubMed  Google Scholar 

  48. Peach C, Mignone VW, Arruda MA, Alcobia DC, Hill SJ, Kilpatrick LE, et al. Molecular pharmacology of VEGF-A isoforms: binding and signalling at VEGFR2. IJMS. 2018;19:1264.

    PubMed  PubMed Central  Google Scholar 

  49. Parent JM, Yu TW, Leibowitz RT, Geschwind DH, Sloviter RS, Lowenstein DH. Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci 1997;17:3727–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Ammothumkandy A, Ravina K, Wolseley V, Tartt AN, Yu P, Corona L, et al. Altered adult neurogenesis and gliogenesis in patients with mesial temporal lobe epilepsy. Nat Neurosci. 2022;25:493–503.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Iyengar SS, LaFrancois JJ, Friedman D, Drew LJ, Denny CA, Burghardt NS, et al. Suppression of adult neurogenesis increases the acute effects of kainic acid. Exp Neurol. 2015;264:135–49.

    CAS  PubMed  Google Scholar 

  52. Lybrand ZR, Goswami S, Zhu J, Jarzabek V, Merlock N, Aktar M, et al. A critical period of neuronal activity results in aberrant neurogenesis rewiring hippocampal circuitry in a mouse model of epilepsy. Nat Commun. 2021;12:1423.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Boldrini M, Fulmore CA, Tartt AN, Simeon LR, Pavlova I, Poposka V, et al. Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell. 2018;22:589–99.e5.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Moreno-Jiménez EP, Flor-García M, Terreros-Roncal J, Rábano A, Cafini F, Pallas-Bazarra N, et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat Med. 2019;25:554–60.

    PubMed  Google Scholar 

  55. Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, et al. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature. 2018;555:377–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Wang W, Wang M, Yang M, Zeng B, Qiu W, Ma Q, et al. Transcriptome dynamics of hippocampal neurogenesis in macaques across the lifespan and aged humans. Cell Res. 2022;32:729–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Franjic D, Skarica M, Ma S, Arellano JI, Tebbenkamp ATN, Choi J, et al. Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron 2021:S0896627321008667. https://doi.org/10.1016/j.neuron.2021.10.036.

  58. Fukumura D, Xavier R, Sugiura T, Chen Y, Park EC, Lu N, et al. Tumor induction of VEGF promoter activity in stromal cells. Cell. 1998;94:715–25.

    CAS  PubMed  Google Scholar 

  59. Smith BM, Saulsbery AI, Sarchet P, Devasthali N, Einstein D, Kirby ED. Oral and injected tamoxifen alter adult hippocampal neurogenesis in female and male mice. eNeuro. 2022;9:ENEURO.0422-21.2022.

    PubMed  PubMed Central  Google Scholar 

  60. Denninger JK, Walker LA, Chen X, Turkoglu A, Pan A, Tapp, Z, et al. Robust transcriptional profiling and identification of differentially expressed genes with low input RNA sequencing of adult hippocampal neural stem and progenitor populations. Front Mol Neurosci. 2022;15:810722.

  61. Denninger JK, Smith BM, Kirby ED. Novel object recognition and object location behavioral testing in mice on a budget. JoVE. 2018:58593. https://doi.org/10.3791/58593.

  62. Rothman JS, Silver RA. NeuroMatic: an integrated open-source software toolkit for acquisition, analysis and simulation of electrophysiological data. Front Neuroinform. 2018;12:14.

    PubMed  PubMed Central  Google Scholar 

  63. Zhao C, Teng EM, Summers RG Jr, Ming G, Gage FH. Distinct morphological stages of dentate granule neuro maturation in the adult mouse hippocampus. J Neurosci. 2006;26:3–11.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank Tony Wyss-Coray for feedback and support in initiating this work. This work was funded by R00NS089938 and R01NS124775 to EDK. MH was funded by the CIRM BRIDGES program. TD and RR were each funded by Ohio State Undergraduate Research Scholarships. FZ and CA were funded by P30NS104177. JCW was funded by R01MH124870.

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  1. Raina Rindani

    Present address: UC Health, Cincinnati, OH, USA

Authors and Affiliations

  1. Department of Psychology, The Ohio State University, Columbus, OH, USA

    Lisa N. Miller, Ashley E. Walters, Jiyeon K. Denninger, Gwendolyn Sebring, Joshua D. Rieskamp, Tianli Ding, Raina Rindani, Megan E. Goldberg, Sakthi Senthilvelan, Abigail Volk & Elizabeth D. Kirby

  2. Department of Neuroscience, The Ohio State University, Columbus, OH, USA

    Meretta A. Hanson, Alec H. Marshall, Aidan C. Johantges, Fangli Zhao, Candice Askwith & Jason C. Wester

  3. Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA

    Manal Hosawi & Kelly S. Chen

  4. Chronic Brain Injury Center, The Ohio State University, Columbus, OH, USA

    Elizabeth D. Kirby

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Contributions

LNM: Formal analysis, investigation, writing—original draft, writing—review & editing, visualization. AEW, AHM, ACJ, GS, TD, RR, KSC, MEG, SS, AV, FZ: Investigation. JKD, MH, JDR: Formal analysis, investigation. MAH: Formal analysis, investigation, writing—original draft. CA, JCW: Writing—original draft, writing & editing, supervision, funding acquisition. EDK: Conceptualization, formal analysis, investigation, writing—original draft, writing—review & editing, visualization, supervision, funding acquisition.

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Correspondence to Elizabeth D. Kirby.

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Miller, L.N., Walters, A.E., Denninger, J.K. et al. Neural stem and progenitor cells support and protect adult hippocampal function via vascular endothelial growth factor secretion. Mol Psychiatry 30, 2152–2167 (2025). https://doi.org/10.1038/s41380-024-02827-8

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