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Tyzack, G., Lakatos, A., & Patani, R. (2016). Human Stem Cell-Derived Astrocytes: Specification and Relevance for Neurological Disorders. Curr Stem Cell Rep, 2, 236–247.
Abstract: Astrocytes abound in the human central nervous system (CNS) and play a multitude of indispensable roles in neuronal homeostasis and regulation of synaptic plasticity. While traditionally considered to be merely ancillary supportive cells, their complex yet fundamental relevance to brain physiology and pathology have only become apparent in recent times. Beyond their myriad canonical functions, previously unrecognised region-specific functional heterogeneity of astrocytes is emerging as an important attribute and challenges the traditional perspective of CNS-wide astrocyte homogeneity. Animal models have undeniably provided crucial insights into astrocyte biology, yet interspecies differences may limit the translational yield of such studies. Indeed, experimental systems aiming to understand the function of human astrocytes in health and disease have been hampered by accessibility to enriched cultures. Human induced pluripotent stem cells (hiPSCs) now offer an unparalleled model system to interrogate the role of astrocytes in neurodegenerative disorders. By virtue of their ability to convey mutations at pathophysiological levels in a human system, hiPSCs may serve as an ideal pre-clinical platform for both resolution of pathogenic mechanisms and drug discovery. Here, we review astrocyte specification from hiPSCs and discuss their role in modelling human neurological diseases.
Keywords: Astrocytes; Disease modelling; Neurodegeneration; Pluripotent stem cells
Notes: PMID:27547709; PMCID:PMC4972864
Ben-Reuven, L., & Reiner, O. (2016). Modeling the autistic cell: iPSCs recapitulate developmental principles of syndromic and nonsyndromic ASD. Dev Growth Differ, 58(5), 481–491.
Abstract: The opportunity to model autism spectrum disorders (ASD) through generation of patient-derived induced pluripotent stem cells (iPSCs) is currently an emerging topic. Wide-scale research of altered brain circuits in syndromic ASD, including Rett Syndrome, Fragile X Syndrome, Angelman's Syndrome and sporadic Schizophrenia, was made possible through animal models. However, possibly due to species differences, and to the possible contribution of epigenetics in the pathophysiology of these diseases, animal models fail to recapitulate many aspects of ASD. With the advent of iPSCs technology, 3D cultures of patient-derived cells are being used to study complex neuronal phenotypes, including both syndromic and nonsyndromic ASD. Here, we review recent advances in using iPSCs to study various aspects of the ASD neuropathology, with emphasis on the efforts to create in vitro model systems for syndromic and nonsyndromic ASD. We summarize the main cellular activity phenotypes and aberrant genetic interaction networks that were found in iPSC-derived neurons of syndromic and nonsyndromic autistic patients.
Keywords: autism; autism spectrum disorder; brain development; disease model; induced pluripotent stem cell
Kelava, I., & Lancaster, M. A. (2016). Dishing out mini-brains: Current progress and future prospects in brain organoid research. Dev Biol, 420(2), 199–209.
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.
Keywords: Cortex; Human brain development; In vitro; Neural differentiation; Neurological disorder; Organoid; Stem cells
Notes: PMID:27402594; PMCID:PMC5161139
Achuta, V. S., Grym, H., Putkonen, N., Louhivuori, V., Karkkainen, V., Koistinaho, J., et al. (2016). Metabotropic glutamate receptor 5 responses dictate differentiation of neural progenitors to NMDA-responsive cells in fragile X syndrome. Dev Neurobiol, .
Abstract: Disrupted metabotropic glutamate receptor 5 (mGluR5) signaling is implicated in many neuropsychiatric disorders, including autism spectrum disorder, found in fragile X syndrome (FXS). Here we report that intracellular calcium responses to the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) are augmented, and calcium-dependent mGluR5-mediated mechanisms alter the differentiation of neural progenitors in neurospheres derived from human induced pluripotent FXS stem cells and the brains of mouse model of FXS. Treatment with the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) prevents an abnormal clustering of DHPG-responsive cells that are responsive to activation of ionotropic receptors in mouse FXS neurospheres. MPEP also corrects morphological defects of differentiated cells and enhanced migration of neuron-like cells in mouse FXS neurospheres. Unlike in mouse neurospheres, MPEP increases the differentiation of DHPG-responsive radial glial cells as well as the subpopulation of cells responsive to both DHPG and activation of ionotropic receptors in human neurospheres. However, MPEP normalizes the FXS-specific increase in the differentiation of cells responsive only to N-methyl-d-aspartate (NMDA) present in human neurospheres. Exposure to MPEP prevents the accumulation of intermediate basal progenitors in embryonic FXS mouse brain suggesting that rescue effects of GluR5 antagonist are progenitor type-dependent and species-specific differences of basal progenitors may modify effects of MPEP on the cortical development. (c) 2016 Wiley Periodicals, Inc. Develop Neurobiol, 2016.
Keywords: 2-methyl-6-(phenylethynyl)-pyridine; fragile X syndrome; glutamatergic neurons; induced pluripotent stem cells; metabotropic glutamate receptor 5
Scheiblich, H., & Bicker, G. (2016). Nitric oxide regulates antagonistically phagocytic and neurite outgrowth inhibiting capacities of microglia. Dev Neurobiol, 76(5), 566–584.
Abstract: Traumatic injury or the pathogenesis of some neurological disorders is accompanied by inflammatory cellular mechanisms, mainly resulting from the activation of central nervous system (CNS) resident microglia. Under inflammatory conditions, microglia up-regulate the inducible isoform of NOS (iNOS), leading to the production of high concentrations of the radical molecule nitric oxide (NO). At the onset of inflammation, high levels of microglial-derived NO may serve as a cellular defense mechanism helping to clear the damaged tissue and combat infection of the CNS by invading pathogens. However, the excessive overproduction of NO by activated microglia has been suggested to govern the inflammation-mediated neuronal loss causing eventually complete neurodegeneration. Here, we investigated how NO influences phagocytosis of neuronal debris by BV-2 microglia, and how neurite outgrowth of human NT2 model neurons is affected by microglial-derived NO. The presence of NO greatly increased microglial phagocytic capacity in a model of acute inflammation comprising lipopolysaccharide (LPS)-activated microglia and apoptotic neurons. Chemical manipulations suggested that NO up-regulates phagocytosis independently of the sGC/cGMP pathway. Using a transwell system, we showed that reactive microglia inhibit neurite outgrowth of human neurons via the generation of large amounts of NO over effective distances in the millimeter range. Application of a NOS blocker prevented the LPS-induced NO production, totally reversed the inhibitory effect of microglia on neurite outgrowth, but reduced the engulfment of neuronal debris. Our results indicate that a rather simple notion of treating excessive inflammation in the CNS by NO synthesis blocking agents has to consider functionally antagonistic microglial cell responses during pharmaceutic therapy.
Keywords: Animals; Apoptosis/physiology; Cell Line; Coculture Techniques; Cyclic GMP/metabolism; Guanylate Cyclase/metabolism; Humans; Inflammation/*metabolism; Lipopolysaccharides; Mice; Microglia/immunology/*physiology; Neurites/*physiology; Neuroimmunomodulation; *Neuronal Outgrowth; Nitric Oxide/*metabolism; Phagocytes/*physiology; *Phagocytosis; Signal Transduction; BV-2 microglia; NT2 model neurons; cGMP; growth cone; nitric oxide synthase