Single-cell analysis reveals T cell infiltration in old neurogenic niches

文章来源： 中国生物技术网 于2019-07-10 19:59:29发布　新闻转自各大新闻媒体，新闻内容并不代表本网立场！如有侵权请联系管理员删除！

首页 　/　 新闻资讯 　/　 新闻资讯
0
 

Single-cell analysis reveals T cell infiltration in old neurogenic niches

Naturevolume 571, pages205–210 (2019) | Download Citation

Article metrics

Citations

0

Altmetric

303

More details

Article metrics

Abstract

The mammalian brain contains neurogenic niches that comprise neural stem cells and other cell types. Neurogenic niches become less functional with age, but how they change during ageing remains unclear. Here we perform single-cell RNA sequencing of young and old neurogenic niches in mice. The analysis of 14,685 single-cell transcriptomes reveals a decrease in activated neural stem cells, changes in endothelial cells and microglia, and an infiltration of T cells in old neurogenic niches. T cells in old brains are clonally expanded and are generally distinct from those in old blood, which suggests that they may experience specific antigens. T cells in old brains also express interferon-γ, and the subset of neural stem cells that has a high interferon response shows decreased proliferation in vivo. We find that T cells can inhibit the proliferation of neural stem cells in co-cultures and in vivo, in part by secreting interferon-γ. Our study reveals an interaction between T cells and neural stem cells in old brains, opening potential avenues through which to counteract age-related decline in brain function.

 

Data availability

All raw sequencing reads for single-cell RNA-seq data (10x Genomics, Smart-seq v4, and Fluidigm C1) as well as bulk RNA-seq data can be found under BioProject PRJNA450425. The command and configuration files, in addition to a list of all versioned dependencies present in the running environment, are available in the Github repository for this paper (https://github.com/gitbuckley/SingleCellAgingSVZ).

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    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).

  2. 2.

    Shen, Q. et al. Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell3, 289–300 (2008).

  3. 3.

    Tavazoie, M. et al. A specialized vascular niche for adult neural stem cells. Cell Stem Cell 3, 279–288 (2008).

  4. 4.

    Codega, P. et al. Prospective identification and purification of quiescent adult neural stem cells from their in vivo niche. Neuron82, 545–559 (2014).

  5. 5.

    Bond, A. M., Ming, G. L. & Song, H. Adult mammalian neural stem cells and neurogenesis: five decades later. Cell Stem Cell 17, 385–395 (2015).

  6. 6.

    Gage, F. H. & Temple, S. Neural stem cells: generating and regenerating the brain. Neuron 80, 588–601 (2013).

  7. 7.

    Maslov, A. Y., Barone, T. A., Plunkett, R. J. & Pruitt, S. C. Neural stem cell detection, characterization, and age-related changes in the subventricular zone of mice. J. Neurosci. 24, 1726–1733 (2004).

  8. 8.

    Luo, J., Daniels, S. B., Lennington, J. B., Notti, R. Q. & Conover, J. C. The aging neurogenic subventricular zone. Aging Cell 5, 139–152 (2006).

  9. 9.

    Chaker, Z., Aïd, S., Berry, H. & Holzenberger, M. Suppression of IGF-I signals in neural stem cells enhances neurogenesis and olfactory function during aging. Aging Cell 14, 847–856 (2015).

  10. 10.

    Enwere, E. et al. Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J. Neurosci. 24, 8354–8365 (2004).

  11. 11.

    Tropepe, V., Craig, C. G., Morshead, C. M. & van der Kooy, D. Transforming growth factor-α null and senescent mice show decreased neural progenitor cell proliferation in the forebrain subependyma. J. Neurosci. 17, 7850–7859 (1997).

  12. 12.

    Molofsky, A. V. et al. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature443, 448–452 (2006).

  13. 13.

    Ahlenius, H., Visan, V., Kokaia, M., Lindvall, O. & Kokaia, Z. Neural stem and progenitor cells retain their potential for proliferation and differentiation into functional neurons despite lower number in aged brain. J. Neurosci. 29, 4408–4419 (2009).

  14. 14.

    Leeman, D. S. et al. Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging.Science 359, 1277–1283 (2018).

  15. 15.

    Silva-Vargas, V., Maldonado-Soto, A. R., Mizrak, D., Codega, P. & Doetsch, F. Age-dependent niche signals from the choroid plexus regulate adult neural stem cells. Cell Stem Cell 19, 643–652 (2016).

  16. 16.

    Ernst, A. et al. Neurogenesis in the striatum of the adult human brain. Cell 156, 1072–1083 (2014).

  17. 17.

    Llorens-Bobadilla, E. et al. Single-cell transcriptomics reveals a population of dormant neural stem cells that become activated upon brain injury. Cell Stem Cell 17, 329–340 (2015).

  18. 18.

    Hochgerner, H. Z., Amit, A., Lönnerberg, P. & Linnarsson, S. Conserved properties of dentate gyrus neurogenesis across postnatal development revealed by single-cell RNA sequencing.Nat. Neurosci. 21, 290–299 (2018).

  19. 19.

    Shin, J. et al. Single-cell RNA-seq with waterfall reveals molecular cascades underlying adult neurogenesis. Cell Stem Cell 17, 360–372 (2015).

  20. 20.

    Dulken, B. W., Leeman, D. S., Boutet, S. C., Hebestreit, K. & Brunet, A. Single-cell transcriptomic analysis defines heterogeneity and transcriptional dynamics in the adult neural stem cell lineage. Cell Rep. 18, 777–790 (2017).

  21. 21.

    Luo, Y. et al. Single-cell transcriptome analyses reveal signals to activate dormant neural stem cells. Cell 161, 1175–1186 (2015).

  22. 22.

    Mizrak, D. et al. Single-cell analysis of regional differences in adult V-SVZ neural stem cell lineages. Cell Rep. 26, 394–406.e5 (2019).

  23. 23.

    Zywitza, V., Misios, A., Bunatyan, L., Willnow, T. E. & Rajewsky, N. Single-cell transcriptomics characterizes cell types in the subventricular zone and uncovers molecular defects impairing adult neurogenesis. Cell Rep. 25, 2457–2469.e8 (2018).

  24. 24.

    Basak, O. et al. Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy. Proc. Natl Acad. Sci. USA 115, E610–E619 (2018).

  25. 25.

    Shi, Z. et al. Single-cell transcriptomics reveals gene signatures and alterations associated with aging in distinct neural stem/progenitor cell subpopulations. Protein Cell 9, 351–364 (2018).

  26. 26.

    Kalamakis, G. et al. Quiescence modulates stem cell maintenance and regenerative capacity in the aging brain. Cell 176, 1407–1419.e14 (2019).

  27. 27.

    Haring, J. S., Badovinac, V. P. & Harty, J. T. Inflaming the CD8+ T cell response. Immunity 25, 19–29 (2006).

  28. 28.

    Montagne, A. et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85, 296–302 (2015).

  29. 29.

    Han, A., Glanville, J., Hansmann, L. & Davis, M. M. Linking T-cell receptor sequence to functional phenotype at the single-cell level. Nat. Biotechnol. 32, 684–692 (2014).

  30. 30.

    Schroder, K., Hertzog, P. J., Ravasi, T. & Hume, D. A. Interferon-gamma: an overview of signals, mechanisms and functions. J. Leukoc. Biol. 75, 163–189 (2004).

  31. 31.

    Yu, Q. et al. Type I interferon controls propagation of long interspersed element-1. J. Biol. Chem. 290, 10191–10199 (2015).

  32. 32.

    De Cecco, M. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73–78 (2019).

  33. 33.

    Pereira, L., Medina, R., Baena, M., Planas, A. M. & Pozas, E. IFN gamma regulates proliferation and neuronal differentiation by STAT1 in adult SVZ niche. Front. Cell. Neurosci. 9, 270 (2015).

  34. 34.

    Baruch, K. et al. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 346, 89–93 (2014).

  35. 35.

    Li, L., Walker, T. L., Zhang, Y., Mackay, E. W. & Bartlett, P. F. Endogenous interferon gamma directly regulates neural precursors in the non-inflammatory brain. J. Neurosci. 30, 9038–9050 (2010).

  36. 36.

    Filiano, A. J. et al. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature 535, 425–429 (2016).

  37. 37.

    Yoo, H., Park, S. H., Ye, S. K. & Kim, M. IFN-γ-induced BST2 mediates monocyte adhesion to human endothelial cells. Cell. Immunol. 267, 23–29 (2011).

  38. 38.

    Holmgren, A. M., Miller, K. D., Cavanaugh, S. E. & Rall, G. F. Bst2/tetherin is induced in neurons by type I interferon and viral infection but is dispensable for protection against neurotropic viral challenge. J. Virol. 89, 11011–11018 (2015).

  39. 39.

    Evans, D. T., Serra-Moreno, R., Singh, R. K. & Guatelli, J. C. BST-2/tetherin: a new component of the innate immune response to enveloped viruses. Trends Microbiol. 18, 388–396 (2010).

  40. 40.

    Constantinescu, C. S., Farooqi, N., O’Brien, K. & Gran, B. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br. J. Pharmacol. 164, 1079–1106 (2011).

  41. 41.

    Weiss, H. A., Millward, J. M. & Owens, T. CD8+ T cells in inflammatory demyelinating disease. J. Neuroimmunol. 191, 79–85 (2007).

  42. 42.

    Raué, H. P., Brien, J. D., Hammarlund, E. & Slifka, M. K. Activation of virus-specific CD8+ T cells by lipopolysaccharide-induced IL-12 and IL-18. J. Immunol. 173, 6873–6881 (2004).

  43. 43.

    Town, T., Tan, J., Flavell, R. A. & Mullan, M. T-cells in Alzheimer’s disease. Neuromolecular Med. 7, 255–264 (2005).

  44. 44.

    Sulzer, D. et al. T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature 546, 656–661 (2017).

  45. 45.

    Buckwalter, M. S. et al. Increased T cell recruitment to the CNS after amyloid β1–42 immunization in Alzheimer’s mice overproducing transforming growth factor-β1. J. Neurosci. 26, 11437–11441 (2006).

  46. 46.

    Ritzel, R. M. et al. Age-associated resident memory CD8 T cells in the central nervous system are primed to potentiate inflammation after ischemic brain injury. J. Immunol. 196, 3318–3330 (2016).

  47. 47.

    Mrdjen, D. et al. High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity 48, 380–395.e6 (2018).

  48. 48.

    Salter, M. W. & Stevens, B. Microglia emerge as central players in brain disease. Nat. Med. 23, 1018–1027 (2017).

  49. 49.

    Pober, J. S. & Sessa, W. C. Evolving functions of endothelial cells in inflammation. Nat. Rev. Immunol. 7, 803–815 (2007).

  50. 50.

    Kokaia, Z., Martino, G., Schwartz, M. & Lindvall, O. Cross-talk between neural stem cells and immune cells: the key to better brain repair? Nat. Neurosci. 15, 1078–1087 (2012).

  51. 51.

    Louveau, A., Harris, T. H. & Kipnis, J. Revisiting the mechanisms of CNS immune privilege. Trends Immunol. 36, 569–577 (2015).

  52. 52.

    Ziv, Y., Avidan, H., Pluchino, S., Martino, G. & Schwartz, M. Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury. Proc. Natl Acad. Sci. USA 103, 13174–13179 (2006).

  53. 53.

    McGavern, D. B., Homann, D. & Oldstone, M. B. A. T cells in the central nervous system: the delicate balance between viral clearance and disease. J. Infect. Dis. 186 (Suppl 2), S145–S151 (2002).

  54. 54.

    Wakim, L. M., Woodward-Davis, A. & Bevan, M. J. Memory T cells persisting within the brain after local infection show functional adaptations to their tissue of residence. Proc. Natl Acad. Sci. USA107, 17872–17879 (2010).

  55. 55.

    Satija, R., Farrell, J. A., Gennert, D., Schier, A. F. & Regev, A. Spatial reconstruction of single-cell gene expression data. Nat. Biotechnol. 33, 495–502 (2015).

  56. 56.

    Doetsch, F., Caillé, I., Lim, D. A., García-Verdugo, J. M. & Alvarez-Buylla, A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703–716 (1999).

  57. 57.

    Capilla-Gonzalez, V., Cebrian-Silla, A., Guerrero-Cazares, H., Garcia-Verdugo, J. M. & Quiñones-Hinojosa, A. Age-related changes in astrocytic and ependymal cells of the subventricular zone. Glia 62, 790–803 (2014).

  58. 58.

    Jin, Y.-H. & Kim, B. S. Isolation of CNS-infiltrating and resident microglial cells. Bio Protoc. 5, e1385 (2015).

  59. 59.

    Stubbington, M. J. T. et al. T cell fate and clonality inference from single-cell transcriptomes. Nat. Methods 13, 329–332 (2016).

  60. 60.

    Nakamura, K. et al. Sequence-specific error profile of Illumina sequencers. Nucleic Acids Res. 39, e90 (2011).

  61. 61.

    Sergushichev, A. A. An algorithm for fast preranked gene set enrichment analysis using cumulative statistic calculation. Preprint at https://www.biorxiv.org/content/10.1101/060012v1(2016).

  62. 62.

    Finak, G. et al. MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data. Genome Biol. 16, 278 (2015).

  63. 63.

    Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010).

  64. 64.

    Bittner, S., Afzali, A. M., Wiendl, H. & Meuth, S. G. Myelin oligodendrocyte glycoprotein (MOG35-55) induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. J. Vis. Exp. 86, 51275 (2014).



扫描上面二维码在移动端打开阅读

热门文章

“谷歌之母”抗癌2年去世 车库孕育万亿帝国
齐鲁制药奥拉帕利首仿获批上市！
肝癌防治新策略？发现 ATF4 蛋白实际作用
机器学习分类自闭症谱系障碍，将有助开启精准治疗标靶研究
有没有突起，差很多！新研究发现 NK 细胞失去抗肿瘤功能的关键机制
以毒攻毒？史丹佛科学家将癌细胞转化为抗癌武器