Reactive astrocytes prevent maladaptive plasticity after ischemic stroke

Aswendt, Markus; Wilhelmsson, Ulrika; Wieters, Frederique; Stokowska, Anna; Schmitt, Felix Johannes; Pallast, Niklas; Pablo, Yolanda de; L, Mohammed; Hoehn, Mathias; Pekna, Marcela; Pekny, Milos

doi:10.1016/j.pneurobio.2021.102199

Cited by 25 publications

(12 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Remodeling of the corticospinal tract and axonal regeneration after a photothrombotic stroke takes longer, and it was unclear whether it reaches the same level as in WT mice ( Liu et al 2014 ). The most recent study demonstrated that after brain injury, GFAP −/− Vim −/− mice showed maladaptive neuronal connectivity associated with impaired functional recovery; i.e., increased synaptic plasticity in the perilesional region and increased loss and gain of neuronal connections in sensorimotor networks ( Aswendt et al 2022 ).…”

Section: The Two-edged Sword Of Vimentin In the Central Nervous Systemmentioning

confidence: 99%

Roles of vimentin in health and disease

et al. 2022

Self Cite

View full text Add to dashboard Cite

More than 27 yr ago, the vimentin knockout (Vim−/−) mouse was reported to develop and reproduce without an obvious phenotype, implying that this major cytoskeletal protein was nonessential. Subsequently, comprehensive and careful analyses have revealed numerous phenotypes in Vim−/− mice and their organs, tissues, and cells, frequently reflecting altered responses in the recovery of tissues following various insults or injuries. These findings have been supported by cell-based experiments demonstrating that vimentin intermediate filaments (IFs) play a critical role in regulating cell mechanics and are required to coordinate mechanosensing, transduction, signaling pathways, motility, and inflammatory responses. This review highlights the essential functions of vimentin IFs revealed from studies of Vim−/− mice and cells derived from them.

show abstract

Section: The Two-edged Sword Of Vimentin In the Central Nervous Systemmentioning

confidence: 99%

Roles of vimentin in health and disease

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Such changes in gene expression may have major implications for cell plasticity in the brain, including the capacity to repair tissue damage and restore lost functionality and subsequent recovery [ 25 ]. As previously noted, astrocytes become reactive in response to cerebral ischemia and undergo functional and morphological changes which elicit both beneficial and detrimental effects [ 14 , 26 ]. Our technology could permit an in-depth focus upon such alterations, along with precipitating factors, and the potential for astrocytes to return to a naive state.…”

Section: Discussionmentioning

confidence: 99%

Microfluidic Model to Evaluate Astrocyte Activation in Penumbral Region following Ischemic Stroke

Denecke

McBain

Hermes

et al. 2022

Cells

View full text Add to dashboard Cite

Stroke is one of the main causes of death in the US and post-stroke treatment options remain limited. Ischemic stroke is caused by a blood clot that compromises blood supply to the brain, rapidly leading to tissue death at the core of the infarcted area surrounded by a hypoxic and nutrient-starved region known as the penumbra. Recent evidence suggests that astrocytes in the penumbral region play a dual role in stroke response, promoting further neural and tissue damage or improving tissue repair depending on the microenvironment. Thus, astrocyte response in the hypoxic penumbra could promote tissue repair after stroke, salvaging neurons in the affected area and contributing to cognitive recovery. However, the complex microenvironment of ischemic stroke, characterized by gradients of hypoxia and nutrients, poses a unique challenge for traditional in vitro models, which in turn hinders the development of novel therapies. To address this challenge, we have developed a novel, polystyrene-based microfluidic device to model the necrotic and penumbral region induced by an ischemic stroke. We demonstrated that when subjected to hypoxia, and nutrient starvation, astrocytes within the penumbral region generated in the microdevice exhibited long-lasting, significantly altered signaling capacity including calcium signaling impairment.

show abstract

“…Astrocyte responses to CNS insults are highly dependent on the pathological context [ 3 ]. Reactive astrocytes restore CNS homeostasis and neuronal functioning thus promoting functional recovery [ 11 , 12 , 16 , 43 ] but reactive astrocytes may also contribute to maladaptive changes or inhibit neuroregeneration [ 4 , 6 , 44 ]. Here we show that the complement peptide C3a exerts differential effects on the expression of Gfap, C3, Nes, Tnf and Il1b in naïve astrocytes, astrocytes after ischemia and astrocytes exposed to LPS.…”

Section: Discussionmentioning

confidence: 99%

“…Astrocytes responding to ischemia upregulate many neurotrophic genes [3] and promote neuronal survival, repair and recovery [11][12][13][14][15][16]. Systemic inflammation, typically modelled by exposure to endotoxin lipopolysaccharide (LPS), leads to the induction of reactive astrocytes that express high amounts of the third complement component (C3) [17] and lipocalin-2, and increase their secretion of long-chain saturated lipids that are toxic to neurons and oligodendrocytes [18].…”

Section: Introductionmentioning

confidence: 99%

Astrocyte Responses to Complement Peptide C3a are Highly Context-Dependent

et al. 2022

Self Cite

View full text Add to dashboard Cite

Astrocytes perform a range of homeostatic and regulatory tasks that are critical for normal functioning of the central nervous system. In response to an injury or disease, astrocytes undergo a pronounced transformation into a reactive state that involves changes in the expression of many genes and dramatically changes astrocyte morphology and functions. This astrocyte reactivity is highly dependent on the initiating insult and pathological context. C3a is a peptide generated by the proteolytic cleavage of the third complement component. C3a has been shown to exert neuroprotective effects, stimulate neural plasticity and promote astrocyte survival but can also contribute to synapse loss, Alzheimer’s disease type neurodegeneration and blood–brain barrier dysfunction. To test the hypothesis that C3a elicits differential effects on astrocytes depending on their reactivity state, we measured the expression of Gfap, Nes, C3ar1, C3, Ngf, Tnf and Il1b in primary mouse cortical astrocytes after chemical ischemia, after exposure to lipopolysaccharide (LPS) as well as in control naïve astrocytes. We found that C3a down-regulated the expression of Gfap, C3 and Nes in astrocytes after ischemia. Further, C3a increased the expression of Tnf and Il1b in naive astrocytes and the expression of Nes in astrocytes exposed to LPS but did not affect the expression of C3ar1 or Ngf. Jointly, these results provide the first evidence that the complement peptide C3a modulates the responses of astrocytes in a highly context-dependent manner.

show abstract

Reactive astrocytes prevent maladaptive plasticity after ischemic stroke

Cited by 25 publications

References 64 publications

Roles of vimentin in health and disease

Roles of vimentin in health and disease

Microfluidic Model to Evaluate Astrocyte Activation in Penumbral Region following Ischemic Stroke

Astrocyte Responses to Complement Peptide C3a are Highly Context-Dependent

Contact Info

Product

Resources

About