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      Asteroid impact: the potential of astrocytes to modulate human neural networks within organoids

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          Abstract

          Astrocytes are a vital cellular component of the central nervous system that impact neuronal function in both healthy and pathological states. This includes intercellular signals to neurons and non-neuronal cells during development, maturation, and aging that can modulate neural network formation, plasticity, and maintenance. Recently, human pluripotent stem cell-derived neural aggregate cultures, known as neurospheres or organoids, have emerged as improved experimental platforms for basic and pre-clinical neuroscience compared to traditional approaches. Here, we summarize the potential capability of using organoids to further understand the mechanistic role of astrocytes upon neural networks, including the production of extracellular matrix components and reactive signaling cues. Additionally, we discuss the application of organoid models to investigate the astrocyte-dependent aspects of neuropathological diseases and to test astrocyte-inspired technologies. We examine the shortcomings of organoid-based experimental platforms and plausible improvements made possible by cutting-edge neuroengineering technologies. These advancements are expected to enable the development of improved diagnostic strategies and high-throughput translational applications regarding neuroregeneration.

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          Most cited references150

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          Reactive astrocyte nomenclature, definitions, and future directions

          Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters—preferably in vivo—plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.
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            In vitro differentiation of transplantable neural precursors from human embryonic stem cells.

            The remarkable developmental potential and replicative capacity of human embryonic stem (ES) cells promise an almost unlimited supply of specific cell types for transplantation therapies. Here we describe the in vitro differentiation, enrichment, and transplantation of neural precursor cells from human ES cells. Upon aggregation to embryoid bodies, differentiating ES cells formed large numbers of neural tube-like structures in the presence of fibroblast growth factor 2 (FGF-2). Neural precursors within these formations were isolated by selective enzymatic digestion and further purified on the basis of differential adhesion. Following withdrawal of FGF-2, they differentiated into neurons, astrocytes, and oligodendrocytes. After transplantation into the neonatal mouse brain, human ES cell-derived neural precursors were incorporated into a variety of brain regions, where they differentiated into both neurons and astrocytes. No teratoma formation was observed in the transplant recipients. These results depict human ES cells as a source of transplantable neural precursors for possible nervous system repair.
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              Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture.

              The human cerebral cortex develops through an elaborate succession of cellular events that, when disrupted, can lead to neuropsychiatric disease. The ability to reprogram somatic cells into pluripotent cells that can be differentiated in vitro provides a unique opportunity to study normal and abnormal corticogenesis. Here, we present a simple and reproducible 3D culture approach for generating a laminated cerebral cortex-like structure, named human cortical spheroids (hCSs), from pluripotent stem cells. hCSs contain neurons from both deep and superficial cortical layers and map transcriptionally to in vivo fetal development. These neurons are electrophysiologically mature, display spontaneous activity, are surrounded by nonreactive astrocytes and form functional synapses. Experiments in acute hCS slices demonstrate that cortical neurons participate in network activity and produce complex synaptic events. These 3D cultures should allow a detailed interrogation of human cortical development, function and disease, and may prove a versatile platform for generating other neuronal and glial subtypes in vitro.
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                Author and article information

                Contributors
                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                22 November 2023
                2023
                : 17
                : 1305921
                Affiliations
                Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute , Houston, TX, United States
                Author notes

                Edited by: Abed Mansour, Hebrew University of Jerusalem, Israel

                Reviewed by: Jeffrey Jones, Salk Institute for Biological Studies, United States; Yanhong Shi, City of Hope Medical Center, United States

                *Correspondence: R. Krencik, rkrencik@ 123456houstonmethodist.org
                Article
                10.3389/fnins.2023.1305921
                10702564
                38075269
                0ffb0cb9-8b9c-4d60-acee-6ca0259c43b2
                Copyright © 2023 Lavekar, Patel, Montalvo-Parra and Krencik.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 02 October 2023
                : 08 November 2023
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 150, Pages: 12, Words: 11447
                Funding
                Funded by: Cancer Prevention and Research Institute of Texas, doi 10.13039/100004917;
                Award ID: RP200655
                Funded by: National Institute on Aging, doi 10.13039/100000049;
                Funded by: National Institute of Neurological Disorders and Stroke, doi 10.13039/100000065;
                Funded by: National Institutes of Health, doi 10.13039/100000002;
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Supported by the National Institute on Aging (R21AG075189) and National Institute of Neurological Disorders and Stroke (R01NS12978) of the National Institutes of Health (NIH). Also supported by Cancer Prevention and Research Institute of Texas (RP200655), Mission Connect (a program of TIRR Foundation; 022–105), and philanthropic funding from Paula and Rusty Walter and Walter Oil & Gas Corp Endowment at Houston Methodist.
                Categories
                Neuroscience
                Review
                Custom metadata
                Neurodegeneration

                Neurosciences
                astrocytes,organoids,human pluripotent stem cells,synapses,extracellular matrix,microglia

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