Induction of astrocyte reactivity promotes neurodegeneration in human pluripotent stem cell models

• Published in: Stem cell reports Vol. 19; no. 8; pp. 1122 - 1136
• Main Authors: Gomes, Cátia, Huang, Kang-Chieh, Harkin, Jade, Baker, Aaron, Hughes, Jason M., Pan, Yanling, Tutrow, Kaylee, VanderWall, Kirstin B., Lavekar, Sailee S., Hernandez, Melody, Cummins, Theodore R., Canfield, Scott G., Meyer, Jason S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.08.2024; Elsevier
• Subjects: astrocyte; differentiation; disease; neurodegeneration; reactivity; stem cell; neurodegeneration; reactivity; disease; differentiation; stem cell; astrocyte
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2024.07.002

Reactive astrocytes are known to exert detrimental effects upon neurons in several neurodegenerative diseases, yet our understanding of how astrocytes promote neurotoxicity remains incomplete, especially in human systems. In this study, we leveraged human pluripotent stem cell (hPSC) models to examine how reactivity alters astrocyte function and mediates neurodegeneration. hPSC-derived astrocytes were induced to a reactive phenotype, at which point they exhibited a hypertrophic profile and increased complement C3 expression. Functionally, reactive astrocytes displayed decreased intracellular calcium, elevated phagocytic capacity, and decreased contribution to the blood-brain barrier. Subsequently, co-culture of reactive astrocytes with a variety of neuronal cell types promoted morphological and functional alterations. Furthermore, when reactivity was induced in astrocytes from patient-specific hPSCs (glaucoma, Alzheimer’s disease, and amyotrophic lateral sclerosis), the reactive state exacerbated astrocytic disease-associated phenotypes. These results demonstrate how reactive astrocytes modulate neurodegeneration, significantly contributing to our understanding of a role for reactive astrocytes in neurodegenerative diseases. •hPSC-derived reactive astrocytes exhibit a predominantly inflammatory phenotype•Reactive astrocytes promote neurodegenerative features in multiple types of neurons•Patient-derived reactive astrocytes result in more robust disease phenotypes In this article, Gomes and colleagues demonstrate the induction of a proinflammatory reactive phenotype in human pluripotent stem cell-derived astrocytes. Reactive astrocytes contributed to neurodegenerative phenotypes in multiple types of neurons, including retinal ganglion cells, cortical neurons, and motor neurons. Further, when differentiated from cell lines derived from glaucoma, Alzheimer’s disease, and ALS patient samples, the reactive state enhanced disease-associated phenotypes.