Reactive astrocytes facilitate vascular repair and remodeling after stroke

Williamson, Michael; Fuertes, Cathleen Joy A.; Dunn, Andrew K.; Drew, Michael R.; Jones, Theresa A.

doi:10.1016/j.celrep.2021.109048

Cited by 109 publications

(96 citation statements)

References 79 publications

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“…We further suggest that establishing more robust connections between reactive astrocyte subsets and BBB dysfunction across diverse animal models and human tissue cohorts will be necessary to continuously shape our understanding for how astrocyte-BBB crosstalk contributes to human neurodegeneration. For example, reactive astrocytes were recently shown to support vascular repair and remodeling after stroke, with worsened outcomes if reactive astrocytes were ablated 96 . This animal model of stroke utilized photoablation rather than artery occlusion, which is the stroke model in which Serpina3n was identified as a reactive astrocyte marker 74 , and Serpina3n was not highlighted in the photoablation datasets.…”

Section: Discussionmentioning

confidence: 99%

Reactive astrocytes transduce blood-brain barrier dysfunction through a TNFα-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin

Kim

Leng

Park

et al. 2022

Preprint

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Astrocytes are critical components of the neurovascular unit that support blood-brain barrier (BBB) function in brain microvascular endothelial cells (BMECs). Transformation of astrocytes to a reactive state in response to injury and disease can be protective or harmful to BBB function, but the underlying mechanisms for these effects remain mostly unclear. Using a human induced pluripotent stem cell (iPSC)-derived coculture model of BMEC-like cells and astrocytes, we found that tumor necrosis factor alpha (TNFα) transitions astrocytes to an inflammatory reactive state through activated STAT3 signaling, whereby the resultant astrocytes disrupt passive BBB function and induce vascular cell adhesion molecule 1 (VCAM-1) expression in the BMEC-like cells. These associations between inflammatory reactive astrocytes, STAT3 activation, and vascular VCAM-1 expression were corroborated in human postmortem tissue. Bioinformatic analyses coupled with CRISPR interference techniques in the iPSC model revealed that inflammatory reactive astrocytes transduce BBB disruption in part through SERPINA3, which encodes alpha 1-antichymotrypsin (α1ACT), a secreted serine protease inhibitor associated with aging, neuroinflammation, and Alzheimer's disease. In murine ex vivo cortical explant cultures, shRNA-mediated silencing of Serpina3n in astrocytes reduced vascular VCAM-1 expression after TNFα challenge. Further, direct treatment with recombinant Serpina3n in both ex vivo explant cultures and the brain in vivo (via intracerebroventricular injection into wild-type mice) was sufficient to induce vascular VCAM-1 expression and reduce tight junction integrity. Overall, our results define the TNFα-STAT3 signaling axis as a driver of an inflammatory reactive astrocyte subtype responsible for BBB dysfunction. Our results also identify α1ACT as an explicit mediator of BBB damage and suggest that inhibition of α1ACT expression or activity could represent a therapeutic avenue for reversing BBB deficits in aging and neurodegenerative disease.

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Section: Discussionmentioning

confidence: 99%

Reactive astrocytes transduce blood-brain barrier dysfunction through a TNFα-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin

Kim

Leng

Park

et al. 2022

Preprint

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“…Astrocytes become reactive after brain/spinal cord injury or neuroinflammation involving the CNS, and reactive astrocytes show morphological changes and upregulation of some intermediate filament proteins such as GFAP, vimentin, and nestin, as well as of ECM molecules such as TN-C and chondroitin sulfate proteoglycans (CSPGs) [90][91][92][93]. It remains under debate as to whether this is a favorable reaction as an essential state for wound healing (good thing and beneficial), or an unfavorable reaction inhibiting axonal regrowth and neurite outgrowth (bad thing and detrimental) [94,95].…”

Section: Integrin Signaling In Reactive Astrocytesmentioning

confidence: 99%

Integrin Signaling in the Central Nervous System in Animals and Human Brain Diseases

Ikeshima-Kataoka

Sugimoto

Tsubokawa

2022

IJMS

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The integrin family is involved in various biological functions, including cell proliferation, differentiation and migration, and also in the pathogenesis of disease. Integrins are multifunctional receptors that exist as heterodimers composed of α and β subunits and bind to various ligands, including extracellular matrix (ECM) proteins; they are found in many animals, not only vertebrates (e.g., mouse, rat, and teleost fish), but also invertebrates (e.g., planarian flatworm, fruit fly, nematodes, and cephalopods), which are used for research on genetics and social behaviors or as models for human diseases. In the present paper, we describe the results of a phylogenetic tree analysis of the integrin family among these species. We summarize integrin signaling in teleost fish, which serves as an excellent model for the study of regenerative systems and possesses the ability for replacing missing tissues, especially in the central nervous system, which has not been demonstrated in mammals. In addition, functions of astrocytes and reactive astrocytes, which contain neuroprotective subpopulations that act in concert with the ECM proteins tenascin C and osteopontin via integrin are also reviewed. Drug development research using integrin as a therapeutic target could result in breakthroughs for the treatment of neurodegenerative diseases and brain injury in mammals.

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“…Ischemic stroke evokes a robust inflammatory response that functions to modulate both acute and chronic responses to ischemic injury [ 57 , 58 ]. This response involves the activation of astrocytes [ 59 , 60 , 61 ], microglia [ 62 , 63 , 64 ], OPCs [ 65 , 66 ] as well as an influx of macrophages and other hematogenous cells across the blood vessel wall [ 67 ]. These cells are recruited to the injured zone through the coordination of cytokines, adhesion molecules and chemokines being secreted by activated cell types [ 67 ].…”

Section: Inflammatory Responsesmentioning

confidence: 99%

Emerging Roles for the Orphan GPCRs, GPR37 and GPR37 L1, in Stroke Pathophysiology

Mouhi

Martin

Owino

2022

IJMS

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Recent studies have shed light on the diverse and complex roles of G-protein coupled receptors (GPCRs) in the pathophysiology of stroke. These receptors constitute a large family of seven transmembrane-spanning proteins that play an intricate role in cellular communication mechanisms which drive both tissue injury and repair following ischemic stroke. Orphan GPCRs represent a unique sub-class of GPCRs for which no natural ligands have been found. Interestingly, the majority of these receptors are expressed within the central nervous system where they represent a largely untapped resource for the treatment of neurological diseases. The focus of this review will thus be on the emerging roles of two brain-expressed orphan GPCRs, GPR37 and GPR37 L1, in regulating various cellular and molecular processes underlying ischemic stroke.

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Reactive astrocytes facilitate vascular repair and remodeling after stroke

Abstract: Highlights d Reactive astrocytes upregulate angiogenesis-related genes after stroke d Astrocytes interact with new vessels in peri-infarct cortex d Ablation of reactive astrocytes disrupts vascular repair and remodeling d Ablation of reactive astrocytes worsens motor recovery

Cited by 109 publications

References 79 publications

Reactive astrocytes transduce blood-brain barrier dysfunction through a TNFα-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin

Reactive astrocytes transduce blood-brain barrier dysfunction through a TNFα-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin

Integrin Signaling in the Central Nervous System in Animals and Human Brain Diseases

Emerging Roles for the Orphan GPCRs, GPR37 and GPR37 L1, in Stroke Pathophysiology

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