Neuroinflammatory astrocyte subtypes in the mouse brain

Hasel, Philip; Rose, Indigo V.L.; Sadick, Jessica S.; Kim, Rachel D; Liddelow, Shane A.

doi:10.1038/s41593-021-00905-6

Cited by 354 publications

(416 citation statements)

References 53 publications

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“…Our single-cell profiling, flow cytometry, and immunofluorescence data suggest that Imoonglia represent a specific cell type that is increased after injury and share the spatial arrangement of SGC surrounding sensory neurons. This may be similar to astrocytes in the CNS, which in addition to their homeostatic functions can undergo an inflammatory transcriptional transition following inflammation after acute insults like stroke ( Zamanian et al, 2012 ), spinal cord injury ( Karimi-Abdolrezaee and Billakanti, 2012 ), and systemic inflammation ( Hasel et al, 2021 ). It is tempting to speculate that Imoonglia may function in immune surveillance in the DRG and specifically in the case of viral infection.…”

Section: Discussionmentioning

confidence: 97%

Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair

Avraham¹,

Feng²,

Ewan³

et al. 2021

eLife

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Sensory neurons with cell bodies in dorsal root ganglia (DRG) represent a useful model to study axon regeneration. Whereas regeneration and functional recovery occurs after peripheral nerve injury, spinal cord injury or dorsal root injury is not followed by regenerative outcomes. Regeneration of sensory axons in peripheral nerves is not entirely cell autonomous. Whether the DRG microenvironment influences the different regenerative capacities after injury to peripheral or central axons remains largely unknown. To answer this question, we performed a single-cell transcriptional profiling of mouse DRG in response to peripheral (sciatic nerve crush) and central axon injuries (dorsal root crush and spinal cord injury). Each cell type responded differently to the three types of injuries. All injuries increased the proportion of a cell type that shares features of both immune cells and glial cells. A distinct subset of satellite glial cells (SGC) appeared specifically in response to peripheral nerve injury. Activation of the PPARα signaling pathway in SGC, which promotes axon regeneration after peripheral nerve injury, failed to occur after central axon injuries. Treatment with the FDA-approved PPARα agonist fenofibrate increased axon regeneration after dorsal root injury. This study provides a map of the distinct DRG microenvironment responses to peripheral and central injuries at the single-cell level and highlights that manipulating non-neuronal cells could lead to avenues to promote functional recovery after CNS injuries or disease.

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Section: Discussionmentioning

confidence: 97%

Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair

Avraham¹,

Feng²,

Ewan³

et al. 2021

eLife

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“…To fulfill the variety of specialized functions required, glia cells are highly specialized according to each CNS region with respect to proteomic signatures, electrophysiology, Ca 2+ signaling, morphology, and proximities to synapses (Tsai et al, 2012;Molofsky et al, 2014;Ben Haim and Rowitch, 2017;Chai et al, 2017). Moreover, even within morphological groups, such as astrocytes, there is heterogeneity of cell types and their pathological responses (John Lin et al, 2017;Hasel et al, 2021) that may also reflect regional differences in the structure and function of the NVU.…”

Section: Overview Of Glial Cells Types and The Neurovascular Unitmentioning

confidence: 99%

The “Neuro-Glial-Vascular” Unit: The Role of Glia in Neurovascular Unit Formation and Dysfunction

Kugler

Greenwood²,

Macdonald³

2021

Front. Cell Dev. Biol.

100

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The neurovascular unit (NVU) is a complex multi-cellular structure consisting of endothelial cells (ECs), neurons, glia, smooth muscle cells (SMCs), and pericytes. Each component is closely linked to each other, establishing a structural and functional unit, regulating central nervous system (CNS) blood flow and energy metabolism as well as forming the blood-brain barrier (BBB) and inner blood-retina barrier (BRB). As the name suggests, the “neuro” and “vascular” components of the NVU are well recognized and neurovascular coupling is the key function of the NVU. However, the NVU consists of multiple cell types and its functionality goes beyond the resulting neurovascular coupling, with cross-component links of signaling, metabolism, and homeostasis. Within the NVU, glia cells have gained increased attention and it is increasingly clear that they fulfill various multi-level functions in the NVU. Glial dysfunctions were shown to precede neuronal and vascular pathologies suggesting central roles for glia in NVU functionality and pathogenesis of disease. In this review, we take a “glio-centric” view on NVU development and function in the retina and brain, how these change in disease, and how advancing experimental techniques will help us address unanswered questions.

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“…As these parenchymal astrocytes do not express PDGFR α , nor any of the other receptor tyrosine kinases known to be targeted by imatinib, including PDGFR β , Abl and c-Kit 14 , it seems likely this is mediated through an indirect mechanism. We speculate these parenchymal astrocytes might be activated by cytokines, including IL-1α, TNF α and C1q, which we found to be strongly upregulated in the vascular fragments after ischemia and normalized by imatinib, since these factors are known to stimulate astrocyte activation 44–46 and potently induce activation of neurotoxic A1 astrocytes 43 . Interestingly though, the astrogliosis dampening effect of imatinib within hours following MCAO did not translate into a differential thickness of the GFAP + astrocyte scar a week after injury.…”

Section: Discussionmentioning

confidence: 73%

Reduced myofibroblast transdifferentiation and fibrotic scarring in ischemic stroke after imatinib treatment

Zeitelhofer

Stefanitsch

Protzmann

et al. 2021

Preprint

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The tyrosine kinase inhibitor imatinib has been reported to improve outcome in patients following ischemic stroke but the exact mechanism remains elusive. Here, utilizing a photothrombotic murine model of middle cerebral artery occlusion (MCAO), we show that imatinib-mediated inhibition of stroke-induced blood-brain barrier (BBB) dysfunction coincided with decreased expression of genes associated with inflammation and fibrosis in the cerebrovasculature. We found that imatinib effectively dampened stroke-induced reactive gliosis and myofibroblast transdifferentiation, whilst having very limited effect on the rest of the glia scar and on peripheral leukocyte infiltration. Further, our data suggest that consolidation of the PDGFRα+ portion of the fibrotic scar in imatinib-treated mice contributes to the improvement in functional outcome compared to the vehicle controls, where the PDGFRα+ scar is expanding. Comparison with human stroke transcriptome databases revealed significant overlap with imatinib-regulated genes, suggesting imatinib may modulate reactive gliosis and fibrotic scarring also in human stroke.

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Neuroinflammatory astrocyte subtypes in the mouse brain

Cited by 354 publications

References 53 publications

Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair

Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair

The “Neuro-Glial-Vascular” Unit: The Role of Glia in Neurovascular Unit Formation and Dysfunction

Reduced myofibroblast transdifferentiation and fibrotic scarring in ischemic stroke after imatinib treatment

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