Reactive astrogliosis in the era of single-cell transcriptomics

Matusova, Zuzana; Hol, Elly M.; Pekny, Milos; Kubista, Mikael; Valihrach, Lukás

doi:10.3389/fncel.2023.1173200

Cited by 22 publications

(16 citation statements)

References 67 publications

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“…CD44 was identified as a particularly robust marker of reactive astrocytes, in various neuropathological contexts [65] and our dataset (Fig.4, Suppl.Fig.10). Surprisingly, we also detected a pronounced upregulation of Cd44 in stroke associated, proliferating OPCs (Fig.2).…”

Section: Resultsmentioning

confidence: 81%

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: Resultsmentioning

confidence: 81%

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

Bormann,

Knoflach,

Poreba

et al. 2023

Preprint

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“…We therefore investigated in which cell type(s) Anxa2, the most upregulated protein in the rpgrip1l -/brain proteome, was expressed. Immunostaining of brain sections revealed a strong Anxa2 process in which astroglial cells react to the perturbed environment, as shown during brain infection, injury, ischemia or neurodegeneration (46)(47)(48). Thus, the strong increase of GFAP staining combined with Anxa2 overexpression in brain ependymal cells of rpgrip1 l-/adult fish strongly suggests that these cells undergo astrogliosis as observed in other animal models following CNS injury (47,49).…”

Section: Astrogliosis Precedes Scoliosis Onset Of Rpgrip1l -/Juvenile...mentioning

confidence: 74%

Astrogliosis and Neuroinflammation Underlie Scoliosis Upon Cilia Dysfunction

Djebar,

Anselme,

Pezeron

et al. 2024

Preprint

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Cilia defects lead to scoliosis in zebrafish, but the underlying pathogenic mechanisms are poorly understood and may diverge depending on the mutated gene. We dissected the mechanisms of scoliosis onset in a zebrafish mutant for therpgrip1lgene encoding a ciliary transition zone protein.rpgrip1lmutant fish developed scoliosis with near-total penetrance but asynchronous onset in juveniles. Taking advantage of this asynchrony, we found that curvature onset was preceded by brain ventricle dilations and concomitant to the perturbation of Reissner fiber polymerization and to the loss of multicilia tufts around the subcommissural organ. Rescue experiments showed that Rpgrip1l was exclusively required infoxj1a-expressing cells to prevent axis curvature. Transcriptomic and proteomic studies identified neuroinflammation associated with increased Annexin levels as a potential mechanism of scoliosis development inrpgrip1ljuveniles. Investigating the cell types associated withannexin2over-expression, we uncovered astrogliosis, arising in glial cells surrounding the diencephalic and rhombencephalic ventricles just before scoliosis onset and increasing with time in severity. Anti-inflammatory drug treatment reduced scoliosis penetrance and severity and this correlated with both reduced astrogliosis and macrophage/microglia enrichment around the diencephalic ventricle. Mutation of thecep290gene encoding another transition zone protein also associated astrogliosis with scoliosis. Thus, we propose that the onset of a feed-forward loop between astrogliosis, induced by perturbed ventricular homeostasis, and immune cells recruitment as a novel pathogenic mechanism of zebrafish scoliosis in ciliary transition zone mutants.

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“…6b). Of particular interest, Tnf (one of the genes with highest degree score in the network) encodes a multifunctional proinflammatory cytokine belonging to the tumor necrosis factor (TNF) superfamily, which has been shown to be one of the main pro-inflammatory cytokines involved in regulation of astrocytes and microglia activation 48,49 . Directly linked with Tnf , other TNF ligands and receptors including Tnfsf9, Tnfrsf11a , and Tnfrsf25 are among the upregulated DEGs linked with astrogliosis gene signatures.…”

Section: Resultsmentioning

confidence: 99%

YY1 mutations disrupt corticogenesis through a cell-type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs

Pereira,

Finazzi,

Rizzuti

et al. 2024

Preprint

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Germline mutations of YY1 cause Gabriele-de Vries syndrome (GADEVS), a neurodevelopmental disorder featuring intellectual disability and a wide range of systemic manifestations. To dissect the cellular and molecular mechanisms underlying GADEVS, we combined large-scale imaging, single-cell multiomics and gene regulatory network reconstruction in 2D and 3D patient-derived physiopathologically relevant cell lineages. YY1 haploinsufficiency causes a pervasive alteration of cell type specific transcriptional networks, disrupting corticogenesis at the level of neural progenitors and terminally differentiated neurons, including cytoarchitectural defects reminiscent of GADEVS clinical features. Transcriptional alterations in neurons propagated to neighboring astrocytes through a major non-cell autonomous pro-inflammatory effect that grounds the rationale for modulatory interventions. Together, neurodevelopmental trajectories, synaptic formation and neuronal-astrocyte cross talk emerged as salient domains of YY1 dosage-dependent vulnerability. Mechanistically, cell-type resolved reconstruction of gene regulatory networks uncovered the regulatory interplay between YY1, NEUROG2 and ETV5 and its aberrant rewiring in GADEVS. Our findings underscore the reach of advanced in vitro models in capturing developmental antecedents of clinical features and exposing their underlying mechanisms to guide the search for targeted interventions.

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Reactive astrogliosis in the era of single-cell transcriptomics

Cited by 22 publications

References 67 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

Astrogliosis and Neuroinflammation Underlie Scoliosis Upon Cilia Dysfunction

YY1 mutations disrupt corticogenesis through a cell-type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs

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