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      Dishing out mini-brains: Current progress and future prospects in brain organoid research

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          Abstract

          The ability to model human brain development in vitro represents an important step in our study of developmental processes and neurological disorders. Protocols that utilize human embryonic and induced pluripotent stem cells can now generate organoids which faithfully recapitulate, on a cell-biological and gene expression level, the early period of human embryonic and fetal brain development. In combination with novel gene editing tools, such as CRISPR, these methods represent an unprecedented model system in the field of mammalian neural development. In this review, we focus on the similarities of current organoid methods to in vivo brain development, discuss their limitations and potential improvements, and explore the future venues of brain organoid research.

          Highlights

          • Brain organoids currently model early human embryonic and fetal brain development to a remarkably high degree.

          • Brain organoids successfully model several neurodevelopmental conditions – microcephaly, idiopathic autism, Zika infection.

          • Modeling later neurodevelopmental events will require improvements to nutrient supply and sustained culture conditions.

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          Most cited references77

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          Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells.

          G Martin (1981)
          This report describes the establishment directly from normal preimplantation mouse embryos of a cell line that forms teratocarcinomas when injected into mice. The pluripotency of these embryonic stem cells was demonstrated conclusively by the observation that subclonal cultures, derived from isolated single cells, can differentiate into a wide variety of cell types. Such embryonic stem cells were isolated from inner cell masses of late blastocysts cultured in medium conditioned by an established teratocarcinoma stem cell line. This suggests that such conditioned medium might contain a growth factor that stimulates the proliferation or inhibits the differentiation of normal pluripotent embryonic cells, or both. This method of obtaining embryonic stem cells makes feasible the isolation of pluripotent cells lines from various types of noninbred embryo, including those carrying mutant genes. The availability of such cell lines should made possible new approaches to the study of early mammalian development.
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            Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system.

            Neurogenesis in the mammalian central nervous system is believed to end in the period just after birth; in the mouse striatum no new neurons are produced after the first few days after birth. In this study, cells isolated from the striatum of the adult mouse brain were induced to proliferate in vitro by epidermal growth factor. The proliferating cells initially expressed nestin, an intermediate filament found in neuroepithelial stem cells, and subsequently developed the morphology and antigenic properties of neurons and astrocytes. Newly generated cells with neuronal morphology were immunoreactive for gamma-aminobutyric acid and substance P, two neurotransmitters of the adult striatum in vivo. Thus, cells of the adult mouse striatum have the capacity to divide and differentiate into neurons and astrocytes.
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              The cell biology of neurogenesis.

              During the development of the mammalian central nervous system, neural stem cells and their derivative progenitor cells generate neurons by asymmetric and symmetric divisions. The proliferation versus differentiation of these cells and the type of division are closely linked to their epithelial characteristics, notably, their apical-basal polarity and cell-cycle length. Here, we discuss how these features change during development from neuroepithelial to radial glial cells, and how this transition affects cell fate and neurogenesis.
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                Author and article information

                Contributors
                Journal
                Dev Biol
                Dev. Biol
                Developmental Biology
                Elsevier
                0012-1606
                1095-564X
                15 December 2016
                15 December 2016
                : 420
                : 2
                : 199-209
                Affiliations
                [0005]MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, CB2 0QH Cambridge, United Kingdom
                Author notes
                [* ]Corresponding author. mlancast@ 123456mrc-lmb.cam.ac.uk
                Article
                S0012-1606(16)30219-6
                10.1016/j.ydbio.2016.06.037
                5161139
                27402594
                66a52e4a-1007-4129-9a02-75382d5f088a
                © 2016 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 19 April 2016
                : 16 June 2016
                : 25 June 2016
                Categories
                Review Article

                Developmental biology
                organoid,cortex,human brain development,in vitro,neurological disorder,neural differentiation,stem cells

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