Assessing Gq-GPCR-induced human astrocyte reactivity using bioengineered neural organoids.
J Cell Biol
; 221(4)2022 02 09.
Article
en En
| MEDLINE
| ID: mdl-35139144
ABSTRACT
Astrocyte reactivity can directly modulate nervous system function and immune responses during disease and injury. However, the consequence of human astrocyte reactivity in response to specific contexts and within neural networks is obscure. Here, we devised a straightforward bioengineered neural organoid culture approach entailing transcription factor-driven direct differentiation of neurons and astrocytes from human pluripotent stem cells combined with genetically encoded tools for dual cell-selective activation. This strategy revealed that Gq-GPCR activation via chemogenetics in astrocytes promotes a rise in intracellular calcium followed by induction of immediate early genes and thrombospondin 1. However, astrocytes also undergo NF-κB nuclear translocation and secretion of inflammatory proteins, correlating with a decreased evoked firing rate of cocultured optogenetic neurons in suboptimal conditions, without overt neurotoxicity. Altogether, this study clarifies the intrinsic reactivity of human astrocytes in response to targeting GPCRs and delivers a bioengineered approach for organoid-based disease modeling and preclinical drug testing.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Organoides
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Astrocitos
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Subunidades alfa de la Proteína de Unión al GTP Gq-G11
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Receptores Acoplados a Proteínas G
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Bioingeniería
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Neuronas
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Cell Biol
Año:
2022
Tipo del documento:
Article