NAD + metabolism drives astrocyte proinflammatory reprogramming in central nervous system autoimmunity DOI Creative Commons

Tom Meyer,

Dor Shimon,

Sawsan Youssef

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(35)

Published: Aug. 22, 2022

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Astrocytes are most abundant glial cells in CNS, and their dysfunction contributes to pathogenesis MS its animal model, experimental autoimmune encephalomyelitis (EAE). Recent advances highlight pivotal role cellular metabolism programming immune responses. However, underlying immunometabolic mechanisms that drive astrocyte pathogenicity remain elusive. Nicotinamide adenine dinucleotide (NAD + ) vital coenzyme involved redox reactions substrate for NAD -dependent enzymes. Cellular levels dynamically controlled by synthesis degradation, dysregulation this balance has been associated with inflammation disease. Here, we demonstrate cell-autonomous generation via salvage pathway regulates function. Inhibition nicotinamide phosphoribosyltransferase (NAMPT), key enzyme pathway, results depletion , inhibits oxidative phosphorylation, limits potential. We identified CD38 as main NADase up-regulated reactive mouse human astrocytes models neuroinflammation MS. Genetic or pharmacological blockade activity augmented levels, suppressed proinflammatory transcriptional reprogramming, impaired chemotactic potential monocytes, ameliorated EAE. found mediated calcineurin/NFAT signaling astrocytes. Thus, NAMPT–NAD –CD38 circuitry controls ability meet energy demands drives expression modules, contributing CNS pathology EAE and, potentially, Our identify candidate therapeutic targets

Language: Английский

What is a cell type and how to define it? DOI Creative Commons
Hongkui Zeng

Cell, Journal Year: 2022, Volume and Issue: 185(15), P. 2739 - 2755

Published: July 1, 2022

Language: Английский

Citations

294
The neurons that restore walking after paralysis DOI Creative Commons
Claudia Kathe, Michael A. Skinnider, Thomas H. Hutson

et al.

Nature, Journal Year: 2022, Volume and Issue: 611(7936), P. 540 - 547

Published: Nov. 9, 2022

Abstract A spinal cord injury interrupts pathways from the brain and brainstem that project to lumbar cord, leading paralysis. Here we show spatiotemporal epidural electrical stimulation (EES) of 1–3 applied during neurorehabilitation 4,5 (EES REHAB ) restored walking in nine individuals with chronic injury. This recovery involved a reduction neuronal activity humans walking. We hypothesized this unexpected reflects activity-dependent selection specific subpopulations become essential for patient walk after To identify these putative neurons, modelled technological therapeutic features underlying EES mice. single-nucleus RNA sequencing 6–9 spatial transcriptomics 10,11 cords mice chart spatially resolved molecular atlas then employed cell type 12,13 prioritization neurons single population excitatory interneurons nested within intermediate laminae emerged. Although are not required before injury, demonstrate they following Augmenting phenocopied enabled by , whereas ablating them prevented occurs spontaneously moderate thus identified recovery-organizing subpopulation is necessary sufficient regain Moreover, our methodology establishes framework using cartography produce complex behaviours.

Language: Английский

Citations

185
Ferroptosis promotes T-cell activation-induced neurodegeneration in multiple sclerosis DOI

Jinyuan Luoqian,

Wenyong Yang, Xulong Ding

et al.

Cellular and Molecular Immunology, Journal Year: 2022, Volume and Issue: 19(8), P. 913 - 924

Published: June 8, 2022

Language: Английский

Citations

126
A cellular taxonomy of the adult human spinal cord DOI Creative Commons
Archana Yadav, Kaya J.E. Matson, Li Li

et al.

Neuron, Journal Year: 2023, Volume and Issue: 111(3), P. 328 - 344.e7

Published: Feb. 1, 2023

The mammalian spinal cord functions as a community of cell types for sensory processing, autonomic control, and movement. While animal models have advanced our understanding cellular diversity, characterizing human biology directly is important to uncover specialized features basic function pathology. Here, we present taxonomy the adult using single-nucleus RNA sequencing with spatial transcriptomics antibody validation. We identified 29 glial clusters 35 neuronal clusters, organized principally by anatomical location. To demonstrate relevance this resource disease, analyzed motoneurons, which degenerate in amyotrophic lateral sclerosis (ALS) other diseases. found that compared neurons, motoneurons are defined genes related size, cytoskeletal structure, ALS, suggesting molecular repertoire underlying their selective vulnerability. include web facilitate further investigations into biology.

Language: Английский

Citations

119
Molecular anatomy of adult mouse leptomeninges DOI Creative Commons

Riikka Pietilä,

Francesca Del Gaudio, Liqun He

et al.

Neuron, Journal Year: 2023, Volume and Issue: 111(23), P. 3745 - 3764.e7

Published: Sept. 29, 2023

Leptomeninges, consisting of the pia mater and arachnoid, form a connective tissue investment barrier enclosure brain. The exact nature leptomeningeal cells has long been debated. In this study, we identify five molecularly distinct fibroblast-like transcriptomes in cerebral leptomeninges; link them to anatomically cell types pia, inner outer arachnoid barrier, dural border layer; contrast sixth transcriptome present choroid plexus median eminence. Newly identified transcriptional markers enabled molecular characterization responsible for adherence layers one another barrier. These also proved useful identifying features development, injury, repair that were preserved or changed after traumatic brain injury. Together, findings highlight value fibroblast subsets their cellular locations toward advancing understanding physiology pathology.

Language: Английский

Citations

69
Harmonized cross-species cell atlases of trigeminal and dorsal root ganglia DOI Creative Commons
Shamsuddin A. Bhuiyan, Mengyi Xu,

Lite Yang

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(25)

Published: June 21, 2024

Sensory neurons in the dorsal root ganglion (DRG) and trigeminal (TG) are specialized to detect transduce diverse environmental stimuli central nervous system. Single-cell RNA sequencing has provided insights into diversity of sensory ganglia cell types rodents, nonhuman primates, humans, but it remains difficult compare across studies species. We thus constructed harmonized atlases DRG TG that describe facilitate comparison 18 neuronal 11 non-neuronal six species 31 datasets. then performed single-cell/nucleus from both human highly regenerative axolotl found atlas also improves type annotation, particularly sparse subtypes. observed transcriptomes neuron subtypes broadly similar vertebrates, expression functionally important neuropeptides channels can vary notably. The resources presented here guide future comparative transcriptomics, simplify cell-type nomenclature differences studies, help prioritize targets for analgesic development.

Language: Английский

Citations

53
Cellular architecture of evolving neuroinflammatory lesions and multiple sclerosis pathology DOI Creative Commons
Petra Kukanja, Christoffer Mattsson Langseth, Leslie A. Kirby

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(8), P. 1990 - 2009.e19

Published: March 20, 2024

Multiple sclerosis (MS) is a neurological disease characterized by multifocal lesions and smoldering pathology. Although single-cell analyses provided insights into cytopathology, evolving cellular processes underlying MS remain poorly understood. We investigated the dynamics of modeling temporal regional rates progression in mouse experimental autoimmune encephalomyelitis (EAE). By performing spatial expression profiling using situ sequencing (ISS), we annotated neighborhoods found centrifugal evolution active lesions. demonstrated that disease-associated (DA)-glia arise independently are dynamically induced resolved over course. Single-cell mapping human archival spinal cords confirmed differential distribution homeostatic DA-glia, enabled deconvolution inactive sub-compartments, identified new lesion areas. establishing resource neuropathology at resolution, our study unveils intricate MS.

Language: Английский

Citations

38
Enhancer AAVs for targeting spinal motor neurons and descending motor pathways in rodents and macaque DOI Creative Commons
Emily Kussick, Nelson Johansen, Naz Taskin

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: unknown, P. 115730 - 115730

Published: May 1, 2025

Experimental access to cell types within the mammalian spinal cord is severely limited by availability of genetic tools. To enable motor neurons (SMNs) and SMN subtypes, we generated single-cell multiome datasets from mouse macaque cords discovered putative enhancers for each neuronal population. We cloned these into adeno-associated viral vectors driving a reporter fluorophore functionally screened them in mouse. extensively characterized most promising candidate rat developed an optimized pan-SMN enhancer virus. Additionally, derivative viruses expressing iCre297T recombinase or ChR2-EYFP labeling functional studies, created single vector with combined elements achieve simultaneous layer 5 extratelencephalic projecting SMNs. This unprecedented toolkit will future investigations type function across species potential therapeutic interventions human neurodegenerative diseases.

Language: Английский

Citations

3
Natural and targeted circuit reorganization after spinal cord injury DOI
Mark A. Anderson, Jordan W. Squair, Matthieu Gautier

et al.

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(12), P. 1584 - 1596

Published: Nov. 17, 2022

Language: Английский

Citations

70
Single cell atlas of spinal cord injury in mice reveals a pro-regenerative signature in spinocerebellar neurons DOI Creative Commons
Kaya J.E. Matson, D. Russ, Claudia Kathe

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Sept. 26, 2022

Abstract After spinal cord injury, tissue distal to the lesion contains undamaged cells that could support or augment recovery. Targeting these requires a clearer understanding of their injury responses and capacity for repair. Here, we use single nucleus RNA sequencing profile how each cell type in lumbar changes after thoracic mice. We present an atlas dynamic across dozens types acute, subacute, chronically injured cord. Using this resource, find rare neurons express signature regeneration response including major population represent spinocerebellar projection neurons. characterize anatomically observed axonal sparing, outgrowth, remodeling cerebellum. Together, work provides key resource studying cellular uncovers spontaneous plasticity neurons, uncovering potential candidate targeted therapy.

Language: Английский

Citations

66