Cerebral organoids model human brain development and microcephaly

Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna 1030, Austria.
Nature (Impact Factor: 41.46). 08/2013; 501(7467). DOI: 10.1038/nature12517
Source: PubMed


The complexity of the human brain has made it difficult to study many brain disorders in model organisms, highlighting the need for an in vitro model of human brain development. Here we have developed a human pluripotent stem cell-derived three-dimensional organoid culture system, termed cerebral organoids, that develop various discrete, although interdependent, brain regions. These include a cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids are shown to recapitulate features of human cortical development, namely characteristic progenitor zone organization with abundant outer radial glial stem cells. Finally, we use RNA interference and patient-specific induced pluripotent stem cells to model microcephaly, a disorder that has been difficult to recapitulate in mice. We demonstrate premature neuronal differentiation in patient organoids, a defect that could help to explain the disease phenotype. Together, these data show that three-dimensional organoids can recapitulate development and disease even in this most complex human tissue.

    • "In these respects, in vitro neuronal connections and circuitry will be therefore somewhat limited by the protocol to recapitulate cortical development in its cellular specification and organisation, particularly in monolayer cultures. However, aspects of cortical cytoarchitecture are remarkably maintained in vitro in particular in 3-dimentional cultures that allow the radial localization of later-born neurons above earlier-born ones (Mariani et al., 2012; Lancaster et al., 2013; Paşca et al., 2015). "
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    ABSTRACT: The in vitro derivation of regionally defined human neuron types from patient-derived stem cells is now established as a resource to investigate human development and disease. Characterisation of such neurons initially focused on the expression of developmentally regulated transcription factors and neural markers, in conjunction with the development of protocols to direct and chart the fate of differentiated neurons. However, crucial to the understanding and exploitation of this technology is to determine the degree to which neurons recapitulate the key functional features exhibited by their native counterparts, essential for determining their usefulness in modelling human physiology and disease in vitro. Here, we review the emerging data concerning functional properties of human pluripotent stem cell-derived excitatory cortical neurons, both in the context of maturation and regional specificity. This article is protected by copyright. All rights reserved.
    No preview · Article · Nov 2015 · The Journal of Physiology
    • "Moreover, from human iPSCs, Lancaster and colleagues were able to generate cerebral organoids, a three dimensional structure that contains areas which resemble specific independent brain regions such as cerebral cortex ([36] and Fig. 1)). Using this model, neuronal differentiation analysis from patients with microcephaly could be performed [36]. The facts that these regions contain neuronal progenitors which can reach a mature state allow the opportunity for example to study cell–cell interactions, time course of cell differentiation in both normal and pathological conditions. "
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    ABSTRACT: Adult cells from patients can be reprogrammed to induced pluripotent stem cells (iPSCs) which successively can be used to obtain specific cells such as neurons. This remarkable breakthrough represents a new way of studying diseases and brought new therapeutic perspectives in the field of Regenerative Medicine. This is particular true in the neurology field, where few techniques are amenable to study the affected tissue of the patient during disease progression and many diseases are lacking neuroprotective therapies or any therapy at all. In this review we discuss the advantages and unresolved issues of cell reprogramming and neuronal differentiation. We reviewed evidence using iPSCs-derived neurons from neurological patients. Focusing on data obtained from Parkinson's disease (PD) patients, we show that iPSC-derived neurons possess morphological and functional characteristics of this disease and build a case for the use of this technology to study PD and other neuropathologies while disease is in progress. These data show the enormous impact that this new technology starts to have on different purposes such as the study and design of future therapies of neurological disease, especially PD. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Jul 2015 · FEBS letters
    • "The region in the white box identifies an area with appropriate apical/basal organization of NPCs and neurons surrounding a ventriclelike structure (Lancaster and others 2013). Bottom images show the development of organoids from iPSCs to fully formed structures (Lancaster and others 2013). (C) Labeling of endogenous proteins in living cells will allow the dynamic study of synaptic components without affecting the function of the synapse. "
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    ABSTRACT: To create a presynaptic terminal, molecular signaling events must be orchestrated across a number of subcellular compartments. In the soma, presynaptic proteins need to be synthesized, packaged together, and attached to microtubule motors for shipment through the axon. Within the axon, transport of presynaptic packages is regulated to ensure that developing synapses receive an adequate supply of components. At individual axonal sites, extracellular interactions must be translated into intracellular signals that can incorporate mobile transport vesicles into the nascent presynaptic terminal. Even once the initial recruitment process is complete, the components and subsequent functionality of presynaptic terminals need to constantly be remodeled. Perhaps most remarkably, all of these processes need to be coordinated in space and time. In this review, we discuss how these dynamic cellular processes occur in neurons of the central nervous system in order to generate presynaptic terminals in the brain. © The Author(s) 2015.
    No preview · Article · Jul 2015 · The Neuroscientist
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