Neuronal vulnerability and multilineage diversity in multiple sclerosis

Schirmer, Lucas; Velmeshev, Dmitry; Holmqvist, Staffan; Kaufmann, Max; Werneburg, Sebastian; Jung, Diane; Vistnes, Stephanie; Stockley, John H.; Young, Adam M. H.; Steindel, Maike; Tung, Brian; Goyal, Nitasha; Bhaduri, Aparna; Mayer, Simone; Engler, Jan Broder; Bayraktar, Ömer; Franklin, R. J. M.; Haeussler, Maximilian; Reynolds, Richard; Schafer, Dorothy P.; Friese, Manuel A.; Shiow, Lawrence R.; Kriegstein, Arnold R.; Rowitch, David H.

doi:10.1038/s41586-019-1404-z

Cited by 400 publications

(573 citation statements)

References 53 publications

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“…Our analysis yielded 24,735 brain nuclei profiles and provide a resource to better understand the complex cellular interactions and gene expression profiles that may contribute to the pathogenesis of CTE. Similar to previous reports using snRNA-seq in other neurological diseases, including Alzheimer's disease (AD), multiple sclerosis (MS), autism spectrum disorder (ASD), and epilepsy (Mathys et al 2019;Grubman et al 2019;Jäkel et al 2019;Schirmer et al 2019;Velmeshev et al 2019), our findings indicate changes in cell types, subpopulations, and gene expression in CTE. Our findings are the first report of molecular and cellular changes at single nucleus resolution in CTE.…”

Section: Introductionsupporting

confidence: 90%

“…To produce a robust tSNE for further analysis, we fine-tuned parameters over various iterations to identify clusters that appeared consistently (Kobak and Berens 2019;Jäkel et al 2019;Mathys et al 2019;Grubman et al 2019;Schirmer et al 2019;Velmeshev et al 2019). After comparing a variety of parameters, we chose 23 principal components and a resolution of 0.8 for input parameters ( Supplementary Fig.…”

Section: Cellular Diversity and Cell-type-specific Changes In Cte Whimentioning

confidence: 99%

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Altered oligodendroglia and astroglia in chronic traumatic encephalopathy

Chancellor

Duke-Cohan

et al. 2020

Preprint

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Chronic traumatic encephalopathy (CTE) is a progressive tauopathy found in contact sport athletes, military veterans, and others exposed to repetitive head injury (McKee et al. 2009(McKee et al. , 2013(McKee et al. , 2016Omalu et al. 2005Omalu et al. , 2006Martland 1928;Critchley 1949). White matter atrophy and axonal loss have been reported in CTE but have not been characterized on a molecular or cellular level (McKee et al. 2013;Holleran et al. 2017;Hsu et al. 2018). Here, we report 24,735 single nucleus RNA-seq profiles from dorsolateral frontal white matter cell nuclei from eight individuals with neuropathologically confirmed CTE and eight age-and sex-matched controls. We identified eighteen transcriptionally distinct nuclei clusters, as well as cell-type-specific differences between conditions. The findings support a global loss of oligodendrocytes (OLs) in CTE, alterations in OL subpopulations, and suggest pathological iron accumulation in OL subpopulations. Total astrocyte number was not different between CTE and controls but showed upregulation of transcripts associated with neuroinflammation. These findings provide novel insight into the molecular and cellular underpinnings of white matter atrophy in CTE, which may lead to an improved understanding of the disease pathogenesis.

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Section: Introductionsupporting

confidence: 90%

Section: Cellular Diversity and Cell-type-specific Changes In Cte Whimentioning

confidence: 99%

Altered oligodendroglia and astroglia in chronic traumatic encephalopathy

Chancellor

Duke-Cohan

et al. 2020

Preprint

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“…To gain new insights into cell populations and cell type-specific differences in gene expression, evolution, neurogenic capability, and variable disease susceptibility, we performed high-coverage single-nucleus RNA sequencing (snRNA-seq) on five anatomically defined subregions of the hippocampal-entorhinal system. These efforts, like similar recent efforts to transcriptomically characterize the postmortem adult human brain (Krishnaswami et al, 2016; Lake et al, 2016; Habib et al, 2017; Lake et al, 2018; Li et al, 2018; Hodge et al, 2019; Mathys et al, 2019; Schirmer et al, 2019; Velmeshev et al, 2019) (including pioneering profiling of HIP (Habib et al, 2017), identified a highly diverse set of neuronal and non-neuronal cell types with clear regional distinctions and implications for human brain function, evolution, and disease.…”

Section: Introductionmentioning

confidence: 85%

Molecular Diversity Among Adult Human Hippocampal and Entorhinal Cells

Franjic

Choi

Škarica

et al. 2020

Preprint

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RESULTS 104Transcriptomic diversity of hippocampal and entorhinal cells 105 To survey the transcriptomic diversity and functional specification of the mesial temporal 106 cortex, we used snRNA-seq to profile five subregions of the hippocampal-entorhinal system 107 6 collected from fresh frozen postmortem brains of clinically unremarkable human donors. These 108 specimens were selected from a larger pool of postmortem human brains based on the quality 109 of isolated nuclei and RNA. Taking into consideration dramatic cytoarchitectonic variations, 110 we microdissected the hippocampal formation (DG, CA2-4, CA1, and subiculum) and EC for 111 a total of five subregions (Fig. 1A). 112 Unbiased isolation of nuclei using our previously described protocol (Li et al., 2018; 113 Zhu et al., 2018) followed by snRNA barcoding, cDNA sequencing and quality filtering yielded 114 108,315 high-quality single-nucleus profiles from all five subregions ( Fig. 1A, S1A-D). 115 Analysis of the expression of genes known to be enriched in major cell subpopulations 116 suggested these included 44,697 neurons, of which 35,768 (80.02%) were glutamatergic 117 excitatory neurons (expressing the gene encoding the vesicular glutamate transporter SLC17A7) 118 and 8,929 (19.98%) were GABAergic inhibitory neurons (expressing the gene encoding the 119 GABA synthesis enzyme GAD1), reflecting the expected 80:20 ratio of these populations. In 120 addition, we identified 63,618 (58.73% of the total population) non-neuronal cells. 121 We next analyzed the transcriptomes of those nuclei on the Uniform Manifold 122 Approximation and Projection (UMAP) layout representing their similarities at cellular 123 granularity ( Fig. 1B-D). Iterative clustering defined 69 transcriptomically distinct cell clusters 124 representing presumptive cell types across all individuals (donors). These transcriptomically 125 diverse subpopulations were organized into a dendrogramatic taxonomy reflecting their gene 126 expression patterns and were subsequently assigned identities commensurate with predicted cell 127 types. This allowed us to identify 26 subtypes of excitatory neurons (Fig. 1E and S2A-B), 23 128 inhibitory neuron subtypes ( Fig. 1E and S2C-D), and 20 non-neuronal cell types and subtypes 129 ( Fig. 1E and S2E-F). Similar single nucleus approaches applied to human neocortical samples 130 7 yielded comparable numbers and distributions of cell populations in medial temporal gyrus 131 (MTG) (Hodge et al., 2019)and dorso-lateral prefrontal cortex (dlPFC) (Li et al., 2018)(Fig. 132 S1E-F). 133Within excitatory neuron subtypes, we found marked transcriptional diversity that 134 reflects differences in the cytoarchitectonic organization among the subregions of the HIP (DG, 135 CA2-4, CA1, and subiculum) and EC (Fig. 1E). For example, in addition to ADCYAP1-136 expressing mossy cells in DG, we found three distinct subclusters of PROX1-expressing granule 137 cells. We also identified excitatory neurons in CA1 and CA2-4 that could be deconstructe...

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“…Murine scRNA‐seq studies have advanced the characterization of OL‐lineage transcriptomic signatures, with several studies identifying intermediate states between progenitors and fully differentiated cells (Artegiani et al, ; Marques et al, ; reviewed in van Bruggen, Agirre, & Castelo‐Branco, ). Human tissue‐based studies that focus on OL‐lineage cells have applied sequencing of nuclei (snRNA‐seq) derived from postmortem tissues from adult “control” donors and individuals with clinical conditions that include MS (Jakel et al, ; Schirmer et al, ), Alzheimer's disease (Mathys et al, ), and autism (Velmeshev et al, ). However, studies of human OL‐lineage development remain limited by the availability of whole cell samples that would permit inclusion of non‐nuclear RNAs, and material that encompasses a wide age span including time of peak myelination.…”

Section: Introductionmentioning

confidence: 99%

Developmental trajectory of oligodendrocyte progenitor cells in the human brain revealed by single cell RNA sequencing

Perlman

Couturier

Yaqubi

et al. 2020

Glia

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Characterizing the developmental trajectory of oligodendrocyte progenitor cells (OPC) is of great interest given the importance of these cells in the remyelination process. However, studies of human OPC development remain limited by the availability of whole cell samples and material that encompasses a wide age range, including time of peak myelination. In this study, we apply single cell RNA sequencing to viable whole cells across the age span and link transcriptomic signatures of oligodendrocyte‐lineage cells with stage‐specific functional properties. Cells were isolated from surgical tissue samples of second‐trimester fetal, 2‐year‐old pediatric, 13‐year‐old adolescent, and adult donors by mechanical and enzymatic digestion, followed by percoll gradient centrifugation. Gene expression was analyzed using droplet‐based RNA sequencing (10X Chromium). Louvain clustering analysis identified three distinct cellular subpopulations based on 5,613 genes, comprised of an early OPC (e‐OPC) group, a late OPC group (l‐OPC), and a mature OL (MOL) group. Gene ontology terms enriched for e‐OPCs included cell cycle and development, for l‐OPCs included extracellular matrix and cell adhesion, and for MOLs included myelination and cytoskeleton. The e‐OPCs were mostly confined to the premyelinating fetal group, and the l‐OPCs were most highly represented in the pediatric age group, corresponding to the peak age of myelination. Cells expressing a signature characteristic of l‐OPCs were identified in the adult brain in situ using RNAScope. These findings highlight the transcriptomic variability in OL‐lineage cells before, during, and after peak myelination and contribute to identifying novel pathways required to achieve remyelination.

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Neuronal vulnerability and multilineage diversity in multiple sclerosis

Cited by 400 publications

References 53 publications

Altered oligodendroglia and astroglia in chronic traumatic encephalopathy

Altered oligodendroglia and astroglia in chronic traumatic encephalopathy

Molecular Diversity Among Adult Human Hippocampal and Entorhinal Cells

Developmental trajectory of oligodendrocyte progenitor cells in the human brain revealed by single cell RNA sequencing

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