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Integration of single-cell and bulk RNA sequencing data reveals key cell types and regulators in traumatic brain injury

  • † These authors contributed equally to this work
  • Received: 12 October 2020 Accepted: 10 January 2021 Published: 14 January 2021
  • Traumatic brain injury (TBI) is a leading cause of disability and mortality worldwide, whose symptoms ranging from mild to severe, even life-threatening. However, specific cell types and key regulators involved in traumatic brain injury have not been well elucidated. In this study, utilizing single-cell RNA-seq (scRNA-seq) data from mice with TBI, we have successfully identified and characterized 13 cell populations including astrocytes, oligodendrocyte, newly formed oligodendrocytes, microglia, two types of endothelial cells, five types of excitatory and two types of inhibitory neurons. Differential expression analysis and gene set enrichment analysis (GSEA) revealed the upregulation of microglia and endothelial markers, along with the downregulation of markers of excitatory neurons in TBI. The cell-cell communication analysis revealed that microglia and endothelial cell might interact through the interaction of Icam1-Il2rg and C1qa-Cd93, and microglia might also communicate with each other via Icam1-Itagm. The autocrine ligand-receptor in microglia might result in activation of TYROBP causal network via Icam1-Itgam. The cell-cell contact between microglia and endothelial cell might activate integrin signaling pathways. Moreover, we also found that genes involved in microglia activation were highly downregulated in Tyrobp/Dap12-deficient microglia, indicating that the upregulation of Tyrobp and TYROBP causal network in microglia might be a candidate therapeutic target in TBI. In contrast, the excitatory neurons were involved in maintaining normal brain function, and their inactivation might cause dysfunction of nervous system in TBI patients. In conclusion, the present study has discerned major cell types such as microglia, endothelial cells and excitatory neurons, and revealed key regulator such as TYROBP, C1QA, and CD93 in TBI, which shall improve our understanding of the pathogenesis of TBI.

    Citation: Rui-zhe Zheng, Jin Xing, Qiong Huang, Xi-tao Yang, Chang-yi Zhao, Xin-yuan Li. Integration of single-cell and bulk RNA sequencing data reveals key cell types and regulators in traumatic brain injury[J]. Mathematical Biosciences and Engineering, 2021, 18(2): 1201-1214. doi: 10.3934/mbe.2021065

    Related Papers:

  • Traumatic brain injury (TBI) is a leading cause of disability and mortality worldwide, whose symptoms ranging from mild to severe, even life-threatening. However, specific cell types and key regulators involved in traumatic brain injury have not been well elucidated. In this study, utilizing single-cell RNA-seq (scRNA-seq) data from mice with TBI, we have successfully identified and characterized 13 cell populations including astrocytes, oligodendrocyte, newly formed oligodendrocytes, microglia, two types of endothelial cells, five types of excitatory and two types of inhibitory neurons. Differential expression analysis and gene set enrichment analysis (GSEA) revealed the upregulation of microglia and endothelial markers, along with the downregulation of markers of excitatory neurons in TBI. The cell-cell communication analysis revealed that microglia and endothelial cell might interact through the interaction of Icam1-Il2rg and C1qa-Cd93, and microglia might also communicate with each other via Icam1-Itagm. The autocrine ligand-receptor in microglia might result in activation of TYROBP causal network via Icam1-Itgam. The cell-cell contact between microglia and endothelial cell might activate integrin signaling pathways. Moreover, we also found that genes involved in microglia activation were highly downregulated in Tyrobp/Dap12-deficient microglia, indicating that the upregulation of Tyrobp and TYROBP causal network in microglia might be a candidate therapeutic target in TBI. In contrast, the excitatory neurons were involved in maintaining normal brain function, and their inactivation might cause dysfunction of nervous system in TBI patients. In conclusion, the present study has discerned major cell types such as microglia, endothelial cells and excitatory neurons, and revealed key regulator such as TYROBP, C1QA, and CD93 in TBI, which shall improve our understanding of the pathogenesis of TBI.


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    [1] M. H. Ahmad, M. Fatima, A. C. Mondal, Influence of microglia and astrocyte activation in the neuroinflammatory pathogenesis of alzheimer's disease: rational insights for the therapeutic approaches, J. Clin. Neurosci., 59 (2018), 6–11.
    [2] M. J. McGinn, J. T. Povlishock, Pathophysiology of Traumatic Brain Injury, Neurosurg. Clin. North Am., 27 (2016), 397–407. doi: 10.1016/j.nec.2016.06.002
    [3] V. Dinet, K. G. Petry, J. Badaut, Brain-immune interactions and neuroinflammation after traumatic brain injury, Front. Neurosci., 13 (2019), 1178.
    [4] T. Maki, K. Hayakawa, L. Pham, C. Xing, E. H. Lo, K. Arai, Biphasic mechanisms of neurovascular unit injury and protection in CNS diseases, CNS Neurol. Disord.: Drug Targets, 12 (2013), 302–315. doi: 10.2174/1871527311312030004
    [5] I. P. Karve, J. M. Taylor, P. J. Crack, The contribution of astrocytes and microglia to traumatic brain injury, Br. J. Pharmacol., 173 (2016), 692–702. doi: 10.1111/bph.13125
    [6] A. D. Bachstetter, B. Xing, L. de Almeida, E. R. Dimayuga, D. M. Watterson, L. J. Van Eldik, Microglial p38α MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Aβ), J. Neuroinflammation, 8 (2011), 79.
    [7] D. Younger, M. Murugan, K. V. Rama Rao, L. J. Wu, N. Chandra, Microglia Receptors in Animal Models of Traumatic Brain Injury, Mol. Neurobiol., 56 (2019), 5202–5228. doi: 10.1007/s12035-018-1428-7
    [8] W. Wang, L. S. Zhang, A. K. Zinsmaier, G. Patterson, E. J. Leptich, S. L. Shoemaker, et al., Neuroinflammation mediates noise-induced synaptic imbalance and tinnitus in rodent models, PLoS Biol., 17 (2019), e3000307.
    [9] S. W. Barger, A. S. Basile, Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function, J. Neurochem., 76 (2010), 846–854.
    [10] O. Thau-Zuchman, E. Shohami, A. G. Alexandrovich, R. R. Leker, Vascular endothelial growth factor increases neurogenesis after traumatic brain injury, J. Cereb. Blood Flow Metab., 30 (2010), 1008–1016. doi: 10.1038/jcbfm.2009.271
    [11] J. Zhang, M. Guan, Q. Wang, J. Zhang, T. Zhou, X. Sun, Single-cell transcriptome-based multilayer network biomarker for predicting prognosis and therapeutic response of gliomas, Briefings Bioinf., 21 (2020), 1080–1097. doi: 10.1093/bib/bbz040
    [12] J. Cheng, J. Zhang, Z. Wu, X. Sun, Inferring microenvironmental regulation of gene expression from single-cell RNA sequencing data using scMLnet with an application to COVID-19, Briefings Bioinf., 2020 (2020), 1–18.
    [13] E. Armingol, A. Officer, O. Harismendy, N. E. Lewis, Deciphering cell-cell interactions and communication from gene expression, Nat. Rev. Genet., (2020) 2020, 1–18.
    [14] W. N. Brandão, M. G. De Oliveira, R. T. Andreoni, H. Nakaya, A. S. Farias, J. P. S. Peron, Neuroinflammation at single cell level: What is new?, J. Leukocyte Biol., 108 (2020), 1129–1137. doi: 10.1002/JLB.3MR0620-035R
    [15] A. Butler, P. Hoffman, P. Smibert, E. Papalexi, R. Satija, Integrating single-cell transcriptomic data across different conditions, technologies, and species, Nat. Biotechnol., 36 (2018), 411–420.
    [16] A. Bhattacherjee, M. N. Djekidel, R. Chen, W. Chen, L. M. Tuesta, Y. Zhang, Cell type-specific transcriptional programs in mouse prefrontal cortex during adolescence and addiction, Nat. Commun., 10 (2019), 4169.
    [17] G. Yu, L. G. Wang, Y. Han, Q. Y. He, clusterProfiler: an R package for comparing biological themes among gene clusters, OMICS: J. Integr. Biol., 16 (2012), 284–287. doi: 10.1089/omi.2011.0118
    [18] J. A. Ramilowski, T. Goldberg, J. Harshbarger, E. Kloppmann, M. Lizio, V. P. Satagopam, et al., A draft network of ligand-receptor-mediated multicellular signalling in human, Nat. Commun., 6 (2015), 7866.
    [19] J. Zhong, L. Jiang, C. Cheng, Z. Huang, H. Zhang, H. Liu, et al., Altered expression of long non-coding RNA and mRNA in mouse cortex after traumatic brain injury, Brain Res., 1646 (2016), 589–600.
    [20] J. F. Zander, A. Münster-Wandowski, I. Brunk, I. Pahner, G. Gómez-Lira, U. Heinemann, et al., Synaptic and vesicular coexistence of VGLUT and VGAT in selected excitatory and inhibitory synapses, J. Neurosci., 30 (2010), 7634–7645.
    [21] A. A. Almad, A. Doreswamy, S. K. Gross, J. P. Richard, Y. Huo, N. Haughey, et al., Connexin 43 in astrocytes contributes to motor neuron toxicity in amyotrophic lateral sclerosis, Glia, 64 (2016), 1154–1169.
    [22] N. S. Mattan, C. A. Ghiani, M. Lloyd, R. Matalon, D. Bok, P. Casaccia, et al., Aspartoacylase deficiency affects early postnatal development of oligodendrocytes and myelination, Neurobiol. Dis., 40 (2010), 432–443.
    [23] A. E. Cole, S. S. Murray, J. Xiao, Bone morphogenetic protein 4 signalling in neural stem and progenitor cells during development and after injury, Stem Cells Int., 2016 (2016), 9260592.
    [24] M. I. Fonseca, S. H. Chu, M. X. Hernandez, M. J. Fang, L. Modarresi, P. Selvan, et al., Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain, J. Neuroinflammation, 14 (2017), 48.
    [25] H. K. Lee, S. K. Chauhan, E. Kay, R. Dana, Flt-1 regulates vascular endothelial cell migration via a protein tyrosine kinase-7-dependent pathway, Blood, 117 (2011), 5762–5771. doi: 10.1182/blood-2010-09-306928
    [26] Y. Cao, K. S. Wilcox, C. E. Martin, T. L. Rachinsky, J. Eberwine, M. A. Dichter, Presence of mRNA for glutamic acid decarboxylase in both excitatory and inhibitory neurons, Proc. Natl. Acad. Sci., 93 (1996), 9844–9849. doi: 10.1073/pnas.93.18.9844
    [27] C. C. Chiu, Y. E. Liao, L. Y. Yang, J. Y. Wang, D. Tweedie, H. K. Karnati, et al., Neuroinflammation in animal models of traumatic brain injury, J. Neurosci. Methods, 272 (2016), 38–49.
    [28] A. F. Ramlackhansingh, D. J. Brooks, R. J. Greenwood, S. K. Bose, F. E. Turkheimer, K. M. Kinnunen, et al., Inflammation after trauma: microglial activation and traumatic brain injury, Ann. Neurol., 70 (2011), 374–383.
    [29] V. E. Johnson, J. E. Stewart, F. D. Begbie, J. Q. Trojanowski, D. H. Smith, W. Stewart, Inflammation and white matter degeneration persist for years after a single traumatic brain injury, Brain, 136 (2013), 28–42. doi: 10.1093/brain/aws322
    [30] A. I. Faden, J. Wu, B. A. Stoica, D. J. Loane, Progressive inflammation-mediated neurodegeneration after traumatic brain or spinal cord injury, Br. J. Pharmacol., 173 (2016), 681–691. doi: 10.1111/bph.13179
    [31] G. W. Kreutzberg, Microglia: a sensor for pathological events in the CNS, Trends Neurosci., 19 (1996), 312–318. doi: 10.1016/0166-2236(96)10049-7
    [32] B. Linnartz-Gerlach, L. G. Bodea, C. Klaus, A. Ginolhac, R. Halder, L. Sinkkonen, et al., TREM2 triggers microglial density and age-related neuronal loss, Glia, 67 (2019), 539–550.
    [33] K. von Kietzell, T. Pozzuto, R. Heilbronn, T. Grössl, H. Fechner, S. Weger, Antibody-mediated enhancement of parvovirus B19 uptake into endothelial cells mediated by a receptor for complement factor C1q, J. Virol., 88 (2014), 8102–8115. doi: 10.1128/JVI.00649-14
    [34] B. Ghebrehiwet, E. I. Peerschke, cC1q-R (calreticulin) and gC1q-R/p33: ubiquitously expressed multi-ligand binding cellular proteins involved in inflammation and infection, Mol. Immunol., 41 (2004), 173–183. doi: 10.1016/j.molimm.2004.03.014
    [35] R. Lugano, K. Vemuri, D. Yu, M. Bergqvist, A. Smits, M. Essand, et al., CD93 promotes β 1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis, J. Clin. Invest., 128 (2018), 3280–3297.
    [36] E. L. Castranio, A. Mounier, C. M. Wolfe, K. N. Nam, N. F. Fitz, F. Letronne, et al., Gene co-expression networks identify Trem2 and Tyrobp as major hubs in human APOE expressing mice following traumatic brain injury, Neurobiol. Dis., 105 (2017), 1–14.
    [37] B. Zhang, C. Gaiteri, L. G. Bodea, Z. Wang, J. McElwee, A. A. Podtelezhnikov, et al., Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease, Cell, 153 (2013), 707–720.
    [38] G. G. Turrigiano, The self-tuning neuron: synaptic scaling of excitatory synapses, Cell, 135 (2008), 422–435. doi: 10.1016/j.cell.2008.10.008
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