Brain and blood single-cell transcriptomics in acute and subacute phases after experimental stroke

García-Bonilla, Lidia; Shahanoor, Ziasmin; Sciortino, Rose; Nazarzoda, Omina; Racchumi, Gianfranco; Iadecola, Costantino; Anrather, Josef

doi:10.1101/2023.03.31.535150

Cited by 4 publications

(2 citation statements)

References 158 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, not all astrocytes after stroke will be neurotoxic, and they are unlikely to be identical. Recent evidence points to multiple transcriptomically-defined reactive astrocytes substates (Boghadadi et al, 2021 ; Hasel et al, 2021 ; Garcia-Bonilla et al, 2023 ). While these substates have not been defined at the functional level, it is most likely they play a key role in the modulation of both the inflammatory response, neuronal maintenance, and tissue preservation in the acute period after stroke.…”

Section: Discussionmentioning

confidence: 99%

Blocking of microglia-astrocyte proinflammatory signaling is beneficial following stroke

Prescott,

Münch,

Brahms

et al. 2024

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Microglia and astrocytes play an important role in the neuroinflammatory response and contribute to both the destruction of neighboring tissue as well as the resolution of inflammation following stroke. These reactive glial cells are highly heterogeneous at both the transcriptomic and functional level. Depending upon the stimulus, microglia and astrocytes mount a complex, and specific response composed of distinct microglial and astrocyte substates. These substates ultimately drive the landscape of the initiation and recovery from the adverse stimulus. In one state, inflammation- and damage-induced microglia release tumor necrosis factor (TNF), interleukin 1α (IL1α), and complement component 1q (C1q), together “TIC.” This cocktail of cytokines drives astrocytes into a neurotoxic reactive astrocyte (nRA) substate. This nRA substate is associated with loss of many physiological astrocyte functions (e.g., synapse formation and maturation, phagocytosis, among others), as well as a gain-of-function release of neurotoxic long-chain fatty acids which kill neighboring cells. Here we report that transgenic removal of TIC led to reduction of gliosis, infarct expansion, and worsened functional deficits in the acute and delayed stages following stroke. Our results suggest that TIC cytokines, and likely nRAs play an important role that may maintain neuroinflammation and inhibit functional motor recovery after ischemic stroke. This is the first report that this paradigm is relevant in stroke and that therapies against nRAs may be a novel means to treat patients. Since nRAs are evolutionarily conserved from rodents to humans and present in multiple neurodegenerative diseases and injuries, further identification of mechanistic role of nRAs will lead to a better understanding of the neuroinflammatory response and the development of new therapies.

show abstract

Section: Discussionmentioning

confidence: 99%

Blocking of microglia-astrocyte proinflammatory signaling is beneficial following stroke

Prescott,

Münch,

Brahms

et al. 2024

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Importantly, not all astrocytes after stroke will be neurotoxic, and they are unlikely to be identical. Recent evidence points to multiple transcriptomically-defined reactive astrocytes substates (Boghadadi et al, 2021; Garcia-Bonilla et al, 2023; Hasel et al, 2021). While these substates have not been defined at the functional level, it is most likely they play a key role in the modulation of both the inflammatory response, neuronal maintenance, and tissue preservation in the acute period after stroke.…”

Section: Discussionmentioning

confidence: 99%

Blocking Formation of Neurotoxic Reactive Astrocytes is Beneficial Following Stroke

Prescott,

Münch,

Brahms

et al. 2023

Preprint

View full text Add to dashboard Cite

Microglia and astrocytes play an important role in the neuroinflammatory response and contribute to both the destruction of neighboring tissue as well as the resolution of inflammation following stroke. These reactive glial cells are highly heterogeneous at both the transcriptomic and functional level. Depending upon the stimulus, microglia and astrocytes mount a complex, and specific response composed of distinct microglial and astrocyte substates. These substates ultimately drive the landscape of the initiation and recovery from the adverse stimulus. In one state, inflammation- and damage-induced microglia release tumor necrosis factor (TNF), interleukin 1a; (IL1a), and complement component 1q (C1q), together TIC. This cocktail of cytokines drives astrocytes into a neurotoxic reactive astrocyte (nRA) substate. This nRA substate is associated with loss of many physiological astrocyte functions (e.g., synapse formation and maturation, phagocytosis, among others), as well as a gain-of-function release of neurotoxic long-chain fatty acids which kill neighboring cells. Here we report that transgenic removal of TIC led to reduction of gliosis, infarct expansion, and worsened functional deficits in the acute and delayed stages following stroke. Our results suggest that TIC cytokines, and likely nRAs play an important role that may maintain neuroinflammation and inhibit functional motor recovery after ischemic stroke. This is the first report that this paradigm is relevant in stroke and that therapies against nRAs may be a novel means to treat patients. Since nRAs are evolutionarily conserved from rodents to humans and present in multiple neurodegenerative diseases and injuries, further identification of mechanistic role of nRAs will lead to a better understanding of the neuroinflammatory response and the development of new therapies.

show abstract

Endothelial cells and macrophages as allies in the healthy and diseased brain

Denes,

Hansen,

Oezorhan

et al. 2024

Acta Neuropathol

View full text Add to dashboard Cite

Diseases of the central nervous system (CNS) are often associated with vascular disturbances or inflammation and frequently both. Consequently, endothelial cells and macrophages are key cellular players that mediate pathology in many CNS diseases. Macrophages in the brain consist of the CNS-associated macrophages (CAMs) [also referred to as border-associated macrophages (BAMs)] and microglia, both of which are close neighbours or even form direct contacts with endothelial cells in microvessels. Recent progress has revealed that different macrophage populations in the CNS and a subset of brain endothelial cells are derived from the same erythromyeloid progenitor cells. Macrophages and endothelial cells share several common features in their life cycle—from invasion into the CNS early during embryonic development and proliferation in the CNS, to their demise. In adults, microglia and CAMs have been implicated in regulating the patency and diameter of vessels, blood flow, the tightness of the blood–brain barrier, the removal of vascular calcification, and the life-time of brain endothelial cells. Conversely, CNS endothelial cells may affect the polarization and activation state of myeloid populations. The molecular mechanisms governing the pas de deux of brain macrophages and endothelial cells are beginning to be deciphered and will be reviewed here.

show abstract

Brain and blood single-cell transcriptomics in acute and subacute phases after experimental stroke

Cited by 4 publications

References 158 publications

Blocking of microglia-astrocyte proinflammatory signaling is beneficial following stroke

Blocking of microglia-astrocyte proinflammatory signaling is beneficial following stroke

Blocking Formation of Neurotoxic Reactive Astrocytes is Beneficial Following Stroke

Endothelial cells and macrophages as allies in the healthy and diseased brain

Contact Info

Product

Resources

About