Glial progenitor heterogeneity and key regulators revealed by single-cell RNA sequencing provide insight to regeneration in spinal cord injury

Wei, Haichao; Wu, Xizi; Withrow, Joseph; Durán, Raquel; Singh, Simranjit; Chaboub, Lesley; Rakshit, Jyotirmoy; Mejia, Julio; Rolfe, Andrew; Herrera, Juan J.; Horner, Philip J.; Wu, Jia Qian

doi:10.1016/j.celrep.2023.112486

Cited by 13 publications

(2 citation statements)

References 102 publications

(120 reference statements)

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“…Intriguingly, a similar enrichment of primary cilium associated genes was previously identified in reactive astrocyte subsets in MS and Parkinson's disease [1,78]. Furthermore, Wei et al have recently characterized a population of astrocyteependymal cells in spinal cord tissue which expanded after acute injury [97]. This population shared several transcriptional similarities with the reactive AC_5 subcluster in our dataset such as the upregulation of Rfx3 and Dnah encoding genes and increased Foxj1 TF activity.…”

Section: Discussionsupporting

confidence: 84%

Single nucleus RNA sequencing reveals glial cell type-specific responses to ischemic stroke

Bormann,

Knoflach,

Poreba

et al. 2023

Preprint

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Reactive neuroglia critically shape the brain’s response to ischemic stroke. However, their phenotypic heterogeneity impedes a holistic understanding of the cellular composition and microenvironment of the early ischemic lesion. Here we generated a single cell resolution transcriptomics dataset of the injured brain during the acute recovery from permanent middle cerebral artery occlusion. This approach unveiled infarction and subtype specific molecular signatures in oligodendrocyte lineage cells and astrocytes, which ranged among the most transcriptionally perturbed cell types in our dataset. Specifically, we characterized and compared infarction restricted proliferating oligodendrocyte precursor cells (OPCs), mature oligodendrocytes and heterogeneous reactive astrocyte populations. Our analyses unveiled unexpected commonalities in the transcriptional response of oligodendrocyte lineage cells and astrocytes to ischemic injury. Moreover, OPCs and reactive astrocytes were involved in a shared immuno-glial cross talk with stroke specific myeloid cells.In situ,osteopontin positive myeloid cells accumulated in close proximity to proliferating OPCs and reactive astrocytes, which expressed the osteopontin receptor CD44, within the perilesional zone specifically.In vitro,osteopontin increased the migratory capacity of OPCs. Collectively, our study highlights molecular cross talk events which might govern the cellular composition and microenvironment of infarcted brain tissue in the early stages of recovery.

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Section: Discussionsupporting

confidence: 84%

Single nucleus RNA sequencing reveals glial cell type-specific responses to ischemic stroke

Bormann,

Knoflach,

Poreba

et al. 2023

Preprint

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“…1; Extended Data Fig. 1) the interesting observation [32][33][34][35] that local OPC can give rise to a small contingent of lesion border astrocytes, noted also in another recent single cell RNAseq study 56 .…”

Section: Phenotypic Features Of Mature Lesion Border Astrocytesmentioning

confidence: 61%

Border-forming wound repair astrocytes

O’Shea,

Ao,

Wang

et al. 2023

Preprint

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Central nervous system (CNS) lesions become surrounded by neuroprotective borders of newly proliferated reactive astrocytes. Fundamental features of these cells are poorly understood. Here, we show that 90% of border-forming astrocytes derive from proliferating Aldh1l1-expressing local astrocytes, and 10% from Pdgfra-expressing oligodendrocyte progenitors in mice. Temporal transcriptome analysis, snRNAseq and immunohistochemistry showed that after CNS injury, local mature astrocytes dedifferentiated, proliferated, and became transcriptionally reprogrammed to permanently altered new functional states, with persisting downregulation of molecules associated with astrocyte-neuron interactions, and upregulation of molecules associated with wound healing, microbial defense, and interactions with stromal and immune cells. Our findings show that at CNS injury sites, local mature astrocytes proliferate and adopt canonical features of essential wound repair cells that persist in adaptive states and are the predominant source of neuroprotective borders that re-establish CNS integrity by separating neural parenchyma from stromal and immune cells as occurs throughout the healthy CNS.

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All the single cells: Single‐cell transcriptomics/epigenomics experimental design and analysis considerations for glial biologists

Prater,

Lin

2024

Glia

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Single‐cell transcriptomics, epigenomics, and other ‘omics applied at single‐cell resolution can significantly advance hypotheses and understanding of glial biology. Omics technologies are revealing a large and growing number of new glial cell subtypes, defined by their gene expression profile. These subtypes have significant implications for understanding glial cell function, cell–cell communications, and glia‐specific changes between homeostasis and conditions such as neurological disease. For many, the training in how to analyze, interpret, and understand these large datasets has been through reading and understanding literature from other fields like biostatistics. Here, we provide a primer for glial biologists on experimental design and analysis of single‐cell RNA‐seq datasets. Our goal is to further the understanding of why decisions are made about datasets and to enhance biologists’ ability to interpret and critique their work and the work of others. We review the steps involved in single‐cell analysis with a focus on decision points and particular notes for glia. The goal of this primer is to ensure that single‐cell ‘omics experiments continue to advance glial biology in a rigorous and replicable way.

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Glial progenitor heterogeneity and key regulators revealed by single-cell RNA sequencing provide insight to regeneration in spinal cord injury

Cited by 13 publications

References 102 publications

Single nucleus RNA sequencing reveals glial cell type-specific responses to ischemic stroke

Single nucleus RNA sequencing reveals glial cell type-specific responses to ischemic stroke

Border-forming wound repair astrocytes

All the single cells: Single‐cell transcriptomics/epigenomics experimental design and analysis considerations for glial biologists

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