Astrocyte reactivity and astrogliosis after spinal cord injury

Okada, Seiji; Hara, Michiya; Kobayakawa, Kazu; Matsumoto, Yoshihiro; Nakashima, Yasuharu

doi:10.1016/j.neures.2017.10.004

Cited by 248 publications

(198 citation statements)

References 20 publications

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“…Astrocytes constitute ≈30% of the cells within the mammalian brain and function as key producers and maintainers of the brain extracellular matrix (ECM) during brain tissue homeostasis . During brain trauma and inflammation, changes in the ECM composition, ECM stiffness, and the introduction of cytokine molecules transform astrocytes from a quiescent to a reactive state. This reactive state is typically characterized by the upregulation of the intermediate filament proteins glial fibrillary acidic protein (GFAP) and vimentin .…”

Section: Introductionmentioning

confidence: 99%

Control of Astrocyte Quiescence and Activation in a Synthetic Brain Hydrogel

Galarza

Crosby

Pak

et al. 2020

Adv Healthcare Materials

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Bioengineers have designed numerous instructive brain extracellular matrix (ECM) environments with tailored and tunable protein compositions and biomechanical properties in vitro to study astrocyte reactivity during trauma and inflammation. However, a major limitation of both protein‐based and synthetic model microenvironments is that astrocytes within fail to retain their characteristic stellate morphology and quiescent state without becoming activated under “normal” culture conditions. Here, a synthetic hydrogel is introduced, which for the first time demonstrates maintenance of astrocyte quiescence and activation on demand. With this synthetic brain hydrogel, the brain‐specific integrin‐binding and matrix metalloprotease‐degradable domains of proteins are shown to control astrocyte star‐shaped morphologies, and an ECM condition that maintains astrocyte quiescence with minimal activation can be achieved. In addition, activation can be induced in a dose‐dependent manner via both defined cytokine cocktails and low molecular weight hyaluronic acid. This synthetic brain hydrogel is envisioned as a new tool to study the physiological role of astrocytes in health and disease.

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Section: Introductionmentioning

confidence: 99%

Control of Astrocyte Quiescence and Activation in a Synthetic Brain Hydrogel

Galarza

Crosby

Pak

et al. 2020

Adv Healthcare Materials

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“…This is most significant in cases where early intervention treatment is not possible, thereby ensuring that patients receive greater access to CNS therapeutics. Importantly, since comparable mechanisms are at play on reactive astrocytes following most types of CNS injuries, the application of this strategy can broadly encompass disorders where astrogliosis and glial scarring are major barriers to neuronal sparing and functional recovery, including traumatic brain [74,75] or spinal cord injuries [12,76,77] and strokes [10,78,79].…”

Section: Discussionmentioning

confidence: 99%

Replicating infant astrocyte behavior in the adult after brain injury improves outcomes

Teo

Boghdadi

Homman‐Ludiye

et al. 2020

Preprint

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Infants and adults respond differently to brain injuries. Specifically, improved neuronal sparing along with reduced astrogliosis and glial scarring often observed earlier in life, likely contributes to improved long-term outcomes. Understanding the underlying mechanisms could enable the recapitulation of neuroprotective effects, observed in infants, to benefit adult patients after brain injuries. We reveal that in primates, Eph/ ephrin signaling contributes to age-dependent reactive astrocyte behavior. Ephrin-A5 expression on astrocytes was more protracted in adults, whereas ephrin-A1 was associated only with infant astrocytes. Furthermore, ephrin-A5 exacerbated major hallmarks of astrocyte reactivity via EphA2 and EphA4 receptors, which was subsequently alleviated by ephrin-A1. Rather than suppressing reactivity, ephrin-A1 signaling shifted astrocytes towards GAP43+ neuroprotection, accounting for improved neuronal sparing in infants. Reintroducing ephrin-A1 after middle-aged ischemic stroke significantly attenuated glial scarring, improved neuronal sparing and preserved circuitry. Therefore, beneficial infant mechanisms can be recapitulated in adults to improve outcomes after CNS injuries.

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“…1fg) 31 . We used the grade of histology reported by the Protein Atlas (ND, low, medium, or high) to assess protein abundance (Table S3- 4). Both approaches, inhouse mass spectrometry and Protein Atlas histology, were combined to determine the relative amounts of proteins present in the brain cortex ( Fig.…”

Section: Characterization Of the Human Brain Ecmmentioning

confidence: 99%

“…Astrocytes constitute approximately 30% 1 of the cells within the mammalian brain and function as key producers and maintainers of the brain extracellular matrix (ECM) during brain tissue homeostasis. 2,3 During brain trauma 4 and inflammation 1,5 , changes in the ECM composition [6][7][8][9][10] , ECM stiffness 11 , and the introduction of cytokine molecules 12 transform astrocytes from a quiescent to a reactive state. This reactive state is typically characterized by the upregulation of the intermediate filament proteins glial fibrillary acidic protein (GFAP) 1-3 and vimentin 13 .…”

mentioning

confidence: 99%

Control of Astrocyte Quiescence and Activation in a Synthetic Brain Hydrogel

Galarza¹,

Crosby²,

Pak

et al. 2019

Preprint

View full text Add to dashboard Cite

Bioengineers designed numerous instructive brain extracellular matrix (ECM) environments that have tailored and tunable protein composition and biomechanics in vitro to study astrocyte reactivity during trauma and inflammation. However, a major limitation of both protein-based and model microenvironments is that astrocytes within fail to retain their characteristic stellate morphology and quiescent state without becoming activated under "normal" culture conditions. Here we introduce a synthetic hydrogel, that for the first time demonstrates maintenance of astrocyte quiescence, and control over activation on demand. With this synthetic brain hydrogel, we show the brain-specific integrin-binding and matrix metalloprotease (MMP)degradable domains of proteins control astrocyte star-shaped morphologies, and we can achieve an ECM condition that maintains astrocyte quiescence with minimal activation. In addition, we can induce activation in a dose-dependent manner via both defined cytokine cocktails and low molecular weight hyaluronic acid. We envision this synthetic brain hydrogel as a new tool to study the physiological role of astrocytes in health and disease.Astrocytes constitute approximately 30% 1 of the cells within the mammalian brain and function as key producers and maintainers of the brain extracellular matrix (ECM) during brain tissue homeostasis. 2,3 During brain trauma 4 and inflammation 1,5 , changes in the ECM composition 6-10 , ECM stiffness 11 , and the introduction of cytokine molecules 12 transform astrocytes from a quiescent to a reactive state. This reactive state is typically characterized by the upregulation of the intermediate filament proteins glial fibrillary acidic protein (GFAP) 1-3 and vimentin 13 . Recent studies 1 have sought to understand the profile and origination of reactive and quiescent astrocytes 12,14 toward developing therapeutics that inhibit astrocyte activation 1 . Yet, these studies are hindered due to the large complexity and lack of control over the in vivo astrocyte microenvironment. Thus, researchers have increasingly sought in vitro models in which to study astrocyte activation. However, a major limitation to the study of normal and healthy astrocytes in vitro is that there is no reproducible system that can maintain astrocytes in a quiescent state to study activation.For this reason, bioengineers have developed defined and controllable cell culture environments in which to study cells in more native-like conditions. Relevant to the brain, astrocytes grown as three-dimensional (3D) organoids 15,16 provide aspects of their native phenotype, such as a stellate morphology and astrocyte cell-to-cell heterogeneity. However, the close cell-cell contact in these organoid culture is an important drawback, as astrocyte processes only overlap in vivo during their reactive state. 2,17 Additionally, this culturing cells as organoids is time consuming 15,18 and does not allow for the customization of ECM cues like stiffness 6,19,20 and ligand density 7,20 present in real tissue. Prot...

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Astrocyte reactivity and astrogliosis after spinal cord injury

Cited by 248 publications

References 20 publications

Control of Astrocyte Quiescence and Activation in a Synthetic Brain Hydrogel

Control of Astrocyte Quiescence and Activation in a Synthetic Brain Hydrogel

Replicating infant astrocyte behavior in the adult after brain injury improves outcomes

Control of Astrocyte Quiescence and Activation in a Synthetic Brain Hydrogel

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