Extracellular matrix and traumatic brain injury

George, Naijil; Geller, Herbert M.

doi:10.1002/jnr.24151

Cited by 90 publications

(79 citation statements)

References 221 publications

(232 reference statements)

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“…In response to TBI, glial cells near the site of injury proliferate and begin modifying the local extracellular environment to mitigate the propagation of damage and facilitate repair (Karve et al, 2016;Pekny and Pekna, 2014). Activated microglia and astrocytes release ECM degrading proteases and deposit ECM components around the injury core (George and Geller, 2018;Wang et al, 2018). The entire process of glial cell accumulation and ECM component deposition is known as glial scarring.…”

Section: Discussionmentioning

confidence: 99%

Multiple particle tracking detects changes in brain extracellular matrix structure and predicts neurodevelopmental age

McKenna

Shackelford

Pontes

et al. 2020

Preprint

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Brain extracellular matrix (ECM) structure mediates many aspects of neuronal function. Probing changes in ECM structure could provide insights into aging and neurological disease. Herein, we demonstrate the ability to characterize changes in brain ECM structure using multiple particle tracking (MPT). MPT was carried out in organotypic rat brain slices to detect induced and naturally occurring changes in ECM structure. Induced degradation of neural ECM led to a significant increase in nanoparticle diffusive ability in the brain extracellular space. For structural changes that occur naturally during development, an inverse relationship existed between age and nanoparticle diffusion. Using the age-dependent dataset, we applied extreme gradient boosting (XGBoost) to generate models capable of classifying nanoparticle trajectories.Collectively, this work demonstrates the utility of MPT combined with machine learning for measuring changes in brain ECM structure and predicting associated complex features such as developmental age.

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Section: Discussionmentioning

confidence: 99%

Multiple particle tracking detects changes in brain extracellular matrix structure and predicts neurodevelopmental age

McKenna

Shackelford

Pontes

et al. 2020

Preprint

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“…Both neurons and astrocytes secrete ECM molecules in the extracellular space and contribute to the state of ECM in the brain (Dzyubenko et al, 2016;Song & Dityatev, 2018). Several studies have reported that the increased activation of astrocytes leads to the secretion of large amounts of ECM molecules after brain injury (George & Geller, 2018), which ultimately result in the formation of the glial scar (Bonneh-Barkay & Wiley, 2009). However, in the aging brain, though there is increased activation of astrocytes, as indicated by elevated levels of GFAP expression (Clarke et al, 2018), the decrease in ECM mRNA expression strongly suggests against the notion that age-dependent increase in astrocytic activation might lead to an increase in the production of ECM related genes.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have shown that there is a gradual age-dependent physiological increase in the neuroinflammation, which is related to activation of astrocytes and microglia (Godbout et al, 2005;Lynch, 2010), and is also thought to be involved in cognitive decline (Pluvinage et al, 2019). Such neuroinflammation is marked by increased expression of astrocytic and microglial markers, such as glial fibrillary acidic protein (GFAP) (Lyons et al, 2009;George & Geller, 2018) and ionized calcium-binding adaptor molecule 1 (IBA1) respectively (Ito et al, 2001) along with the upregulation of proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) (Lynch, 2010). Additionally, pathological conditions such as brain injury also lead to increased activation of astrocytes that stimulates secretion of several ECM molecules that ultimately results in the formation of the glial scar (Fawcett & Asher, 1999;Beggah et al, 2005;Cregg et al, 2014;George & Geller, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Such neuroinflammation is marked by increased expression of astrocytic and microglial markers, such as glial fibrillary acidic protein (GFAP) (Lyons et al, 2009;George & Geller, 2018) and ionized calcium-binding adaptor molecule 1 (IBA1) respectively (Ito et al, 2001) along with the upregulation of proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) (Lynch, 2010). Additionally, pathological conditions such as brain injury also lead to increased activation of astrocytes that stimulates secretion of several ECM molecules that ultimately results in the formation of the glial scar (Fawcett & Asher, 1999;Beggah et al, 2005;Cregg et al, 2014;George & Geller, 2018). However, whether the increased activation of astrocytes under the conditions of physiological aging will also result in increased ECM production remain to be investigated.…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic mechanism of carbohydrate sulfotransferase 3 (CHST3) downregulation in the aging brain

Baidoe-Ansah

Sakib

Jia

et al. 2019

Preprint

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Neural extracellular matrix (ECM) is a complex molecular meshwork surrounding neurons and glial cells in the extracellular space. Structural and functional state of ECM in the brain is tightly regulated by various components of neural ECM such as hyaluronic acid, chondroitin sulfate proteoglycans, link proteins, tenascins, various matrix-modifying enzymes such as chondroitin sulfate synthases and carbohydrate sulfotransferase together with matrix-degrading enzymes. Agedependent accumulation of ECM molecules is implicated in the age-associated decline in synaptic and cognitive functions. Understanding age-associated changes in the expression of genes involved in regulating various components of ECM can provide an insight into the role of ECM in the aging brain. Hence, in this study, we compared the expression levels of ECM regulating genes in three groups of mice: 2-3 months old mice (2-3M), 22-to 26-month-old mice (22-26M) and more than 30-month-old mice (>30M). Using qPCR, we discovered that in the hippocampus of >30M old mice, the majority of ECM related genes are downregulated, while genes related to neuroinflammation are highly upregulated. This pattern was accompanied by a decrease in cognitive performance of the >30M old mice and was most correlated among ECM-related genes with the downregulation of carbohydrate sulfotransferase 3 (CHST3) gene expression. Interestingly, in 24-26M mice, no general decrease in the expression of ECM related genes was observed, although we still found the upregulation in neuroinflammatory genes and downregulation of CHST3. Further analysis of epigenetic mechanisms revealed a decrease in H3K4me3, three methyl groups at the lysine 4 on the histone H3 proteins, associated with the promoter region of CHST3 gene in non-neuronal (NeuN-negative) but not in neuronal (NeuNpositive) cells. We conclude that in 22-26 M old brains there are minor changes in expression of the studied bona fide neural ECM genes but there is a prominent epigenetic dysregulation of the CHST3 gene responsible for 6-sulfation of chondroitin sulfates, which may lead to impaired brain plasticity and cognitive decline.

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“…Radiation-induced changes in the brain and tumor microenvironment injury resulting in molecular, cellular, and functional changes that can facilitate tumor aggressiveness upon recurrence (8). Such changes include decreased vascularity, innate immune activation, and altered pharmacokinetics, pharmacodynamics, and therapeutic efficacy of chemotherapy agents (9)(10)(11)(12). Additionally, irradiation (IR) generated reactive oxygen and nitrogen species (ROS/NOS) play havoc with cellular proteins, DNA and phospholipid membrane (13).…”

Section: Introductionmentioning

confidence: 99%

Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma

Gupta

Vučković

Zhang

et al. 2020

Preprint

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AbstractGlioblastoma (GBM) is uniformly fatal with a one year median survival rate, despite the best available treatment, including radiotherapy (RT). Impacts of prior RT on tumor recurrence are poorly understood but may increase tumor aggressiveness. Metabolic changes have been investigated in radiation-induced brain injury; however, the tumor-promoting effect following prior radiation is lacking. Since RT is vital to GBM management, we quantified the tumor-promoting effects of prior radiotherapy (RT) on patient-derived intracranial GBM xenografts and characterized the metabolic alterations associated with the protumorigenic microenvironment. Human xenografts (GBM143) were implanted into nude mice 24h following 20Gy cranial radiation vs. sham animals. Tumors in pre-radiated mice were more proliferative and more infiltrative, yielding faster mortality (p<0.0001). Histologic evaluation of tumor associated macrophage/microglia (TAMs) revealed cells with a more fully activated ameboid morphology in pre-radiated animals. Microdialyzates from the radiated brain at the margin of tumor infiltration contralateral to the site of implantation were analyzed by unsupervised liquid chromatography-mass spectrometry (LC-MS). In pre-radiated animals, metabolites known to be associated with tumor progression (like, modified nucleotides and polyols) were identified. Whole-tissue metabolomic analysis of the pre-radiated brain microenvironment for metabolic alterations in a separate cohort of nude mice using 1H-NMR revealed significant decrease in levels of antioxidants (glutathione (GSH) and ascorbate (ASC)), NAD+, TCA intermediates, and increased ATP and GTP. Glutathione and ASC showed highest VIPpred (1.65) in OPLS-DA analysis. Involvement of ASC catabolism was further confirmed by GC-MS. To assess longevity of radiation effects, we compared survival with implantation occuring 2 months vs. 24h following radiation, finding worse survival in animals implanted at 2 months. These radiation-induced alterations are consistent with a chronic disease-like microenvironment characterized by reduced levels of antioxidants and NAD+, as well as elevated extracellular ATP and GTP serving as chemoattractants, promoting cell motility and vesicular secretion with decreased levels of GSH and ASC exacerbating oxidative stress. Taken together, these data suggest that IR induces tumor-permissive changes in the microenvironment with metabolomic alterations that may facilitate tumor aggressiveness with important implications for recurrent glioblastoma. Harnessing these metabolomic insights may provide opportunities to attenuate RT-associated aggressiveness of recurrent GBM.

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Extracellular matrix and traumatic brain injury

Cited by 90 publications

References 221 publications

Multiple particle tracking detects changes in brain extracellular matrix structure and predicts neurodevelopmental age

Multiple particle tracking detects changes in brain extracellular matrix structure and predicts neurodevelopmental age

Epigenetic mechanism of carbohydrate sulfotransferase 3 (CHST3) downregulation in the aging brain

Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma

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