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

McComish, Sarah F.; O’Sullivan, Julia; Copas, Adina Mac Mahon; Imiolek, Magdalena; Boyle, Noreen T.; Crompton, Lucy A.; Lane, Jon D.; Caldwell, Maeve A.

Abstract

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.

• Journal Article Type: Article
• Acceptance Date: Sep 27, 2024
• Online Publication Date: Oct 3, 2024
• Publication Date: Dec 31, 2024
• Deposit Date: Nov 6, 2024
• Publicly Available Date: Oct 4, 2025
• Journal: Experimental Neurology
• Print ISSN: 0014-4886
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 382
• Article Number: 114979
• DOI: https://doi.org/10.1016/j.expneurol.2024.114979
• Public URL: https://uwe-repository.worktribe.com/output/13404813
• Additional Information: This article is maintained by: Elsevier; Article Title: Reactive astrocytes generated from human iPSC are pro-inflammatory and display altered metabolism; Journal Title: Experimental Neurology; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.expneurol.2024.114979; Content Type: article; Copyright: © 2024 Published by Elsevier Inc.