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  1. Artikel ; Online: Modeling the Inflammatory Response of Traumatic Brain Injury Using Human Induced Pluripotent Stem Cell Derived Microglia.

    Alam, Aftab / Singh, Tanya / Kayhanian, Saeed / Tjerkaski, Jonathan / Garcia, Núria Marcó / Carpenter, Keri L H / Patani, Rickie / Lindblad, Caroline / Thelin, Eric P / Syed, Yasir Ahmed / Helmy, Adel

    Journal of neurotrauma

    2023  Band 40, Heft 19-20, Seite(n) 2164–2173

    Abstract: The neuroinflammatory response after traumatic brain injury (TBI) is implicated as a key mediator of secondary injury in both the acute and chronic periods after primary injury. Microglia are the key innate immune cell in the central nervous system, ... ...

    Abstract The neuroinflammatory response after traumatic brain injury (TBI) is implicated as a key mediator of secondary injury in both the acute and chronic periods after primary injury. Microglia are the key innate immune cell in the central nervous system, responding to injury with the release of cytokines and chemokines. In this context, we aimed to characterize the downstream cytokine response of human induced pluripotent stem cell (iPSC)-derived microglia when stimulated with five separate cytokines identified after human TBI. The iPSC-derived microglia were exposed to interleukin (IL)-1β, IL-4, IL-6, IL-10, and tumor necrosis factor (TNF) in the concentration ranges identified in clinical TBI studies. The downstream cytokine response was measured against a panel of 37 separate cytokines over a 72h time-course. The secretome revealed concentration-, time- and combined concentration and time-dependent downstream responses. TNF appeared to be the strongest inducer of downstream cytokine changes (51), followed by IL-1β (26) and IL-4 (19). IL-10 (11) and IL-6 (10) produced fewer responses. We also compare these responses with our previous studies of iPSC-derived neuronal and astrocyte cultures and the
    Mesh-Begriff(e) Animals ; Humans ; Microglia/pathology ; Interleukin-10 ; Induced Pluripotent Stem Cells ; Interleukin-6 ; Interleukin-4 ; Disease Models, Animal ; Brain Injuries, Traumatic/complications ; Cytokines ; Brain Injuries/complications ; Tumor Necrosis Factor-alpha
    Chemische Substanzen Interleukin-10 (130068-27-8) ; Interleukin-6 ; Interleukin-4 (207137-56-2) ; Cytokines ; Tumor Necrosis Factor-alpha
    Sprache Englisch
    Erscheinungsdatum 2023-07-25
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 645092-1
    ISSN 1557-9042 ; 0897-7151
    ISSN (online) 1557-9042
    ISSN 0897-7151
    DOI 10.1089/neu.2022.0508
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Astrocytes display cell autonomous and diverse early reactive states in familial amyotrophic lateral sclerosis.

    Taha, Doaa M / Clarke, Benjamin E / Hall, Claire E / Tyzack, Giulia E / Ziff, Oliver J / Greensmith, Linda / Kalmar, Bernadett / Ahmed, Mhoriam / Alam, Aftab / Thelin, Eric P / Garcia, Nuria Marco / Helmy, Adel / Sibley, Christopher R / Patani, Rickie

    Brain : a journal of neurology

    2022  Band 145, Heft 2, Seite(n) 481–489

    Abstract: Amyotrophic lateral sclerosis is a rapidly progressive and fatal disease. Although astrocytes are increasingly recognized contributors to the underlying pathogenesis, the cellular autonomy and uniformity of astrocyte reactive transformation in different ... ...

    Abstract Amyotrophic lateral sclerosis is a rapidly progressive and fatal disease. Although astrocytes are increasingly recognized contributors to the underlying pathogenesis, the cellular autonomy and uniformity of astrocyte reactive transformation in different genetic forms of amyotrophic lateral sclerosis remain unresolved. Here we systematically examine these issues by using highly enriched and human induced pluripotent stem cell-derived astrocytes from patients with VCP and SOD1 mutations. We show that VCP mutant astrocytes undergo cell-autonomous reactive transformation characterized by increased expression of complement component 3 (C3) in addition to several characteristic gene expression changes. We then demonstrate that isochronic SOD1 mutant astrocytes also undergo a cell-autonomous reactive transformation, but that this is molecularly distinct from VCP mutant astrocytes. This is shown through transcriptome-wide analyses, identifying divergent gene expression profiles and activation of different key transcription factors in SOD1 and VCP mutant human induced pluripotent stem cell-derived astrocytes. Finally, we show functional differences in the basal cytokine secretome between VCP and SOD1 mutant human induced pluripotent stem cell-derived astrocytes. Our data therefore reveal that reactive transformation can occur cell autonomously in human amyotrophic lateral sclerosis astrocytes and with a striking degree of early molecular and functional heterogeneity when comparing different disease-causing mutations. These insights may be important when considering astrocyte reactivity as a putative therapeutic target in familial amyotrophic lateral sclerosis.
    Mesh-Begriff(e) Amyotrophic Lateral Sclerosis/metabolism ; Astrocytes/metabolism ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Mutation/genetics ; Superoxide Dismutase/genetics ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics
    Chemische Substanzen Superoxide Dismutase (EC 1.15.1.1) ; Superoxide Dismutase-1 (EC 1.15.1.1)
    Sprache Englisch
    Erscheinungsdatum 2022-01-18
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awab328
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Human stem cell-derived astrocytes exhibit region-specific heterogeneity in their secretory profiles.

    Clarke, Benjamin E / Taha, Doaa M / Ziff, Oliver J / Alam, Aftab / Thelin, Eric P / García, Núria Marcó / Helmy, Adel / Patani, Rickie

    Brain : a journal of neurology

    2020  Band 143, Heft 10, Seite(n) e85

    Mesh-Begriff(e) Astrocytes/metabolism ; Cell Differentiation/physiology ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Neural Stem Cells/metabolism
    Sprache Englisch
    Erscheinungsdatum 2020-09-07
    Erscheinungsland England
    Dokumenttyp Letter ; Research Support, Non-U.S. Gov't
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awaa258
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: Focally administered succinate improves cerebral metabolism in traumatic brain injury patients with mitochondrial dysfunction.

    Khellaf, Abdelhakim / Garcia, Nuria Marco / Tajsic, Tamara / Alam, Aftab / Stovell, Matthew G / Killen, Monica J / Howe, Duncan J / Guilfoyle, Mathew R / Jalloh, Ibrahim / Timofeev, Ivan / Murphy, Michael P / Carpenter, T Adrian / Menon, David K / Ercole, Ari / Hutchinson, Peter J / Carpenter, Keri Lh / Thelin, Eric P / Helmy, Adel

    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

    2021  Band 42, Heft 1, Seite(n) 39–55

    Abstract: Following traumatic brain injury (TBI), raised cerebral lactate/pyruvate ratio (LPR) reflects impaired energy metabolism. Raised LPR correlates with poor outcome and mortality following TBI. We prospectively recruited patients with TBI requiring ... ...

    Abstract Following traumatic brain injury (TBI), raised cerebral lactate/pyruvate ratio (LPR) reflects impaired energy metabolism. Raised LPR correlates with poor outcome and mortality following TBI. We prospectively recruited patients with TBI requiring neurocritical care and multimodal monitoring, and utilised a tiered management protocol targeting LPR. We identified patients with persistent raised LPR despite adequate cerebral glucose and oxygen provision, which we clinically classified as cerebral 'mitochondrial dysfunction' (MD). In patients with TBI and MD, we administered disodium 2,3-
    Mesh-Begriff(e) Adult ; Brain/metabolism ; Brain Injuries, Traumatic/drug therapy ; Brain Injuries, Traumatic/metabolism ; Energy Metabolism/drug effects ; Female ; Humans ; Intracranial Pressure/drug effects ; Lactic Acid/metabolism ; Male ; Microdialysis ; Middle Aged ; Mitochondria/metabolism ; Nuclear Magnetic Resonance, Biomolecular ; Pyruvic Acid/metabolism ; Succinic Acid/administration & dosage
    Chemische Substanzen Lactic Acid (33X04XA5AT) ; Pyruvic Acid (8558G7RUTR) ; Succinic Acid (AB6MNQ6J6L)
    Sprache Englisch
    Erscheinungsdatum 2021-09-08
    Erscheinungsland United States
    Dokumenttyp Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 604628-9
    ISSN 1559-7016 ; 0271-678X
    ISSN (online) 1559-7016
    ISSN 0271-678X
    DOI 10.1177/0271678X211042112
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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