Reactive astrocytes generated from human iPSC are pro-inflammatory and display altered metabolism.

Autor: McComish SF; Discipline of Physiology & School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland., O'Sullivan J; Discipline of Physiology & School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland., Copas AMM; Discipline of Physiology & School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland., Imiolek M; Discipline of Physiology & School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland., Boyle NT; Discipline of Physiology & School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland., Crompton LA; Regenerative Medicine Laboratory, School of Clinical Sciences, University of Bristol, Bristol, UK; Cell Biology Laboratories, School of Biochemistry, University of Bristol, Bristol, UK., Lane JD; Cell Biology Laboratories, School of Biochemistry, University of Bristol, Bristol, UK., Caldwell MA; Discipline of Physiology & School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland. Electronic address: maeve.caldwell@tcd.ie.
Jazyk: angličtina
Zdroj: Experimental neurology [Exp Neurol] 2024 Dec; Vol. 382, pp. 114979. Date of Electronic Publication: 2024 Sep 30.
DOI: 10.1016/j.expneurol.2024.114979
Abstrakt: Astrocytes are the most abundant type of glial cell in the central nervous system and they play pivotal roles in both normal health and disease. Their dysfunction is detrimental to many brain related pathologies. Under pathological conditions, such as Alzheimer's disease, astrocytes adopt an activated reactive phenotype which can contribute to disease progression. A prominent risk factor for many neurodegenerative diseases is neuroinflammation which is the purview of glial cells, such as astrocytes and microglia. Human in vitro models have the potential to reveal relevant disease specific mechanisms, through the study of individual cell types such as astrocytes or the addition of specific factors, such as those secreted by microglia. The aim of this study was to generate human cortical astrocytes, in order to assess their protein and gene expression, examine their reactivity profile in response to exposure to the microglial secreted factors IL-1α, TNFα and C1q and assess their functionality in terms of calcium signalling and metabolism. The successfully differentiated and stimulated reactive astrocytes display increased IL-6, RANTES and GM-CSF secretion, and increased expression of genes associated with reactivity including, IL-6, ICAM1, LCN2, C3 and SERPINA3. Functional assessment of these reactive astrocytes showed a delayed and sustained calcium response to ATP and a concomitant decrease in the expression of connexin-43. Furthermore, it was demonstrated these astrocytes had an increased glycolytic capacity with no effect on oxidative phosphorylation. These findings not only increase our understanding of astrocyte reactivity but also provides a functional platform for drug discovery.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024. Published by Elsevier Inc.)
Databáze: MEDLINE
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