@article{5708ac0698e74577ae43c35fe2f80ebe,
title = "Assessing Gq-GPCR–induced human astrocyte reactivity using bioengineered neural organoids",
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.",
keywords = "Cell signaling, Neuroscience, Stem cells",
author = "Caroline Cvetkovic and Rajan Patel and Arya Shetty and Hogan, {Matthew K.} and Morgan Anderson and Nupur Basu and Samira Aghlara-Fotovat and Srivathsan Ramesh and Debosmita Sardar and Omid Veiseh and Ward, {Michael E.} and Benjamin Deneen and Horner, {Philip J.} and Robert Krencik",
note = "Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health (NIH) under Award Number R21AG064567. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Research was also supported by Mission Connect (a program of TIRR Foundation; 019-114), The Michael J. Fox Foundation for Parkinson{\textquoteright}s Research (17871), and Cancer Prevention and Research Institute of Texas Award (RP200655). We thank the RNA Core and Center for Bioenergetics at Houston Methodist Research Institute for technical support, Dr. Gillian Hamilton and Dr. Yi-Lan Weng at Houston Methodist Research Institute for helpful discussions, Bushra Biba at Novogene Corporation for assistance with biostatistics, and Dr. Sung Yun Jung and Antrix Jain at the Mass Spectrometry Proteomics Core at Baylor College of Medicine (BCM) for their assistance. The BCM Mass Spectrometry Proteomics Core is supported by the Dan L. Duncan Comprehensive Cancer Center NIH award (P30 CA125123), Cancer Prevention and Research Institute of Texas Core Facility Award (RP170005), and NIH High End Instrument award (S10 OD026804). Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health (NIH) under Award Number R21AG064567. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Research was also supported by Mission Connect (a program of TIRR Foundation; 019-114), The Michael J. Fox Foundation for Parkinson{\textquoteright}s Research (17871), and Cancer Prevention and Research Institute of Texas Award (RP200655). We thank the RNA Core and Center for Bioenergetics at Houston Methodist Research Institute for technical support, Dr. Gillian Hamilton and Dr. Yi-Lan Weng at Houston Methodist Research Institute for helpful discussions, Bushra Biba at Novogene Corporation for assistance with biostatistics, and Dr. Sung Yun Jung and Antrix Jain at the Mass Spectrometry Proteomics Core at Baylor College of Medicine (BCM) for their assistance. The BCM Mass Spectrometry Proteomics Core is supported by the Dan L. Duncan Comprehensive Cancer Center NIH award (P30 CA125123), Cancer Prevention and Research Institute of Texas Core Facility Award (RP170005), and NIH High End Instrument award (S10 OD026804). The authors declare no competing interests.",
year = "2022",
month = apr,
day = "4",
doi = "10.1083/jcb.202107135",
language = "English (US)",
volume = "221",
journal = "Journal of Cell Biology",
issn = "0021-9525",
publisher = "Rockefeller University Press",
number = "4",
}