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Journal Article•DOI•

Cerebral organoids model human brain development and microcephaly

Madeline A. Lancaster1, Magdalena Renner1, Carol Anne Martin2, Daniel Wenzel1, Louise S. Bicknell2, Matthew E. Hurles3, Tessa Homfray4, Josef M. Penninger1, Andrew P. Jackson2, Juergen A. Knoblich1 •
Austrian Academy of Sciences1, University of Edinburgh2, Wellcome Trust Sanger Institute3, St George's, University of London4
19 Sep 2013-Nature (Nature Publishing Group)-Vol. 501, Iss: 7467, pp 373-379
TL;DR: A human pluripotent stem cell-derived three-dimensional organoid culture system that develops various discrete, although interdependent, brain regions that include a cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes is developed.
Abstract: 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

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Citations
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Journal Article•DOI•
Microfluidic organs-on-chips

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Sangeeta N. Bhatia1, Donald E. Ingber2•
Brigham and Women's Hospital1, Wyss Institute for Biologically Inspired Engineering2
01 Aug 2014-Nature Biotechnology
TL;DR: A microfluidic cell culture device created with microchip manufacturing methods that contains continuously perfused chambers inhabited by living cells arranged to simulate tissue- and organ-level physiology has great potential to advance the study of tissue development, organ physiology and disease etiology.
Abstract: Organ-level physiology is recapitulated in vitro by culturing cells in perfused, microfluidic devices.

2,339 citations

Journal Article•DOI•
Modeling Development and Disease with Organoids

[...]

Hans Clevers1•
Royal Netherlands Academy of Arts and Sciences1
16 Jun 2016-Cell
TL;DR: 3D culture technology allow embryonic and adult mammalian stem cells to exhibit their remarkable self-organizing properties, and the resulting organoids reflect key structural and functional properties of organs such as kidney, lung, gut, brain and retina, and hold promise to predict drug response in a personalized fashion.

1,810 citations

Cites background from "Cerebral organoids model human brai..."

  • ...Lancaster and Knoblich took this approach to a next level by generating cerebral organoids, or ‘‘mini-brains’’: single neural organoids containing representations of several different brain regions (Lancaster et al., 2013)....

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  • ...The corresponding iPS cells made significant smaller ‘‘mini-brains,’’ containing only occasional neuroepithelial regionswith signs of remature neural differentiation, a phenotype that could be rescued by reintroducing the CDK5RAP2 protein (Lancaster et al., 2013)....

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  • ...Lancaster and Knoblich took this approach to a next level by generating cerebral organoids, or ‘‘mini-brains’’: single neural organoids containing representations of several different brain regions (Lancaster et al., 2013)....

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  • ...Since post-radiation hyposalivation often leads to irreversible and untreatable (A) A complex morphology with heterogeneous regions containing neural progenitors (SOX2, red) and neurons (TUJ1, green) is apparent (Lancaster et al., 2013)....

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  • ...A ‘‘Mini-Brain’’ Generated from PSCs (A) A complex morphology with heterogeneous regions containing neural progenitors (SOX2, red) and neurons (TUJ1, green) is apparent (Lancaster et al., 2013)....

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Journal Article•DOI•
Organogenesis in a dish: modeling development and disease using organoid technologies.

[...]

Madeline A. Lancaster1, Juergen A. Knoblich1•
Austrian Academy of Sciences1
18 Jul 2014-Science
TL;DR: These studies illustrated two key events in structural organization during organogenesis: cell sorting out and spatially restricted lineage commitment, which are recapitulated in organoids, which self-assemble to form the cellular organization of the organ itself.
Abstract: Classical experiments performed half a century ago demonstrated the immense self-organizing capacity of vertebrate cells. Even after complete dissociation, cells can reaggregate and reconstruct the original architecture of an organ. More recently, this outstanding feature was used to rebuild organ parts or even complete organs from tissue or embryonic stem cells. Such stem cell-derived three-dimensional cultures are called organoids. Because organoids can be grown from human stem cells and from patient-derived induced pluripotent stem cells, they have the potential to model human development and disease. Furthermore, they have potential for drug testing and even future organ replacement strategies. Here, we summarize this rapidly evolving field and outline the potential of organoid technology for future biomedical research.

1,737 citations

Journal Article•DOI•
Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure

[...]

Xuyu Qian1, Ha Nam Nguyen1, Mingxi M. Song1, Christopher Hadiono1, Sarah C. Ogden2, Christy Hammack2, Bing Yao3, Gregory R. Hamersky1, Fadi Jacob1, Chun Zhong1, Ki Jun Yoon1, William J. Jeang1, Li Lin3, Yujing Li3, Jai Thakor1, Daniel A. Berg1, Ce Zhang1, Eunchai Kang1, Michael Chickering1, David W. Nauen1, Cheng-Ying Ho4, Cheng-Ying Ho5, Zhexing Wen1, Kimberly M. Christian1, Pei Yong Shi6, Brady J. Maher1, Hao Wu3, Peng Jin3, Hengli Tang2, Hongjun Song, Guo Li Ming •
Johns Hopkins University School of Medicine1, Florida State University2, Emory University3, Children's National Medical Center4, George Washington University5, University of Texas Medical Branch6
19 May 2016-Cell
TL;DR: A miniaturized spinning bioreactor (SpinΩ) is developed to generate forebrain-specific organoids from human iPSCs that recapitulate key features of human cortical development, including progenitor zone organization, neurogenesis, gene expression, and, notably, a distinct human-specific outer radial glia cell layer.

1,526 citations

Cites background or methods or result from "Cerebral organoids model human brai..."

  • ...…pioneering studies showed that cerebral organoid systems offer improved growth conditions for 3D tissue, leading to a more representative model of the developing human brain (Danjo et al., 2011; Kadoshima et al., 2013; Lancaster et al., 2013; Mariani et al., 2015; Pasca et al., 2015)....

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  • ...One recent advance in cerebral organoid technology was the adoption of a spinning bioreactor to facilitate nutrient and oxygen absorption, which enables formation of longer neuroepithelium-like zones and supports growth of large, complex organoids that more closely resemble the developing human brain than had been achieved by previous approaches (Lancaster et al., 2013)....

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  • ...Second, the current cerebral organoid methodology (“intrinsic protocol”) is based on cell self-assembly without external control, and thus each organoid is typically comprised of diverse cell types found in forebrain, hindbrain, and retina (Lancaster et al., 2013)....

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  • ...This and other human cerebral organoid technologies (Kadoshima et al., 2013; Lancaster et al., 2013; Cell....

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  • ...Second, the current cerebral organoid methodology (‘‘intrinsic protocol’’) is based on cell self-assembly without external control, and thus each organoid is typically comprised of diverse cell types found in forebrain, hindbrain, and retina (Lancaster et al., 2013)....

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Journal Article•DOI•
Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture

[...]

Anca M. Pasca1, Steven A. Sloan1, Laura E. Clarke1, Yuan Tian2, Christopher D. Makinson1, Nina Huber1, Chul Hoon Kim3, Jin-Young Park1, Nancy A. O'Rourke1, Khoa D. Nguyen1, Stephen J. Smith1, John R. Huguenard1, Daniel H. Geschwind2, Ben A. Barres1, Sergiu P. Paşca1 •
Stanford University1, University of California, Los Angeles2, Yonsei University3
01 Jul 2015-Nature Methods
TL;DR: A simple and reproducible 3D culture approach for generating a laminated cerebral cortex–like structure, named human cortical spheroids (hCSs), from pluripotent stem cells, which demonstrate that cortical neurons participate in network activity and produce complex synaptic events.
Abstract: 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.

1,104 citations

References
More filters
Journal Article•DOI•
Growth and targeting of subplate axons and establishment of major cortical pathways [published erratum appears in J Neurosci 1993 Mar;13(3):following table of contents]

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J. A. De Carlos1, Dennis D.M. O'Leary1•
Salk Institute for Biological Studies1
01 Apr 1992-The Journal of Neuroscience
TL;DR: In rats, the axonal populations that establish the internal capsule are identified, and the potential role of subplate axons in the development of cortical efferent and afferent projections is characterized.
Abstract: In the developing mammalian neocortex, the first postmitotic neurons form the "preplate" superficial to the neuroepithelium. The preplate is later split into a marginal zone (layer 1) and subplate by cortical plate neurons that form layers 2-6. Cortical efferent axons from layers 5 and 6 and cortical afferent axons from thalamus pass between cortex and subcortical structures through the internal capsule. Here, we identify in rats the axonal populations that establish the internal capsule, and characterize the potential role of subplate axons in the development of cortical efferent and afferent projections. The early growth of cortical efferent and afferent axons was studied using 1-1'-dioctodecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Dil) as an anterograde and retrograde tracer in aldehyde-fixed brains of embryonic rats. Cortical axons first enter the nascent internal capsule on embryonic day (E) 14 and originate from lateral and anterior cortex; axons from posterior cortex extend rostrally but do not yet exit cortex. The labeled axons, tipped by growth cones with complex morphologies, take a pathway deep to the preplate. Preplate neurons extend these early cortical efferents, based on the developmental stage of the cortex, and on their location and morphology. Most of these cells later occupy the subplate. Cortical plate neurons extend axons into the internal capsule by E16. En route to the internal capsule, cortical plate axons take the same path as the earlier-growing preplate axons, through the intermediate zone deep to subplate. Subplate axons reach thalamus by E16; the first cortical plate axons enter thalamus about a day later. Thalamic axons enter cortex by E16, prior to other cortical afferents. On E15, both preplate and thalamic axons reach the midpoint of the internal capsule. To determine the subcortical distribution of subplate axons, we used Dil as a retrograde tracer in aldehyde-fixed brains and fast blue and rhodamine-B-isothiocyanate as in vivo retrograde markers in neonatal rats. Tracers were injected into the superior colliculus, the principal midbrain target of layer 5 neurons, at times before, during, and after the arrival of cortical axons, or into the subcortical pathway of primary layer 5 axons at two points, the cerebral peduncle caudal to the internal capsule, and the pyramidal decussation at the junction of the hindbrain and spinal cord, at times shortly after the passing of cortical axons. In every case, the labeled neurons are confined to layer 5; subplate neurons are not labeled.(ABSTRACT TRUNCATED AT 400 WORDS)

349 citations

Journal Article•DOI•
Nucleokinesis in Neuronal Migration

[...]

Li-Huei Tsai1, Joseph G. Gleeson2•
Howard Hughes Medical Institute1, University of California, San Diego2
05 May 2005-Neuron
TL;DR: Converging studies suggest nucleokinesis appears to require many of the same cytoskeletal and signaling molecules used in cell mitosis, and requires cytoplasmic dynein, cell polarity genes, and microtubule-associated proteins that coordinate microtubules remodeling.

341 citations

Journal Article•DOI•
Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex

[...]

Francesco Bedogni1, Rebecca D. Hodge2, Gina E. Elsen3, Branden R. Nelson3, Ray A. M. Daza3, Richard P. Beyer2, Theo K. Bammler2, John L.R. Rubenstein4, Robert F. Hevner2 •
Seattle Children's Research Institute1, University of Washington2, Boston Children's Hospital3, University of California, San Francisco4
20 Jul 2010-Proceedings of the National Academy of Sciences of the United States of America
TL;DR: Tbr1 coordinately regulates regional and laminar identity of postmitotic cortical neurons, and exhibits ectopic axon projections to the hypothalamus and cerebral peduncle.
Abstract: Areas and layers of the cerebral cortex are specified by genetic programs that are initiated in progenitor cells and then, implemented in postmitotic neurons. Here, we report that Tbr1, a transcription factor expressed in postmitotic projection neurons, exerts positive and negative control over both regional (areal) and laminar identity. Tbr1 null mice exhibited profound defects of frontal cortex and layer 6 differentiation, as indicated by down-regulation of gene-expression markers such as Bcl6 and Cdh9. Conversely, genes that implement caudal cortex and layer 5 identity, such as Bhlhb5 and Fezf2, were up-regulated in Tbr1 mutants. Tbr1 implements frontal identity in part by direct promoter binding and activation of Auts2, a frontal cortex gene implicated in autism. Tbr1 regulates laminar identity in part by downstream activation or maintenance of Sox5, an important transcription factor controlling neuronal migration and corticofugal axon projections. Similar to Sox5 mutants, Tbr1 mutants exhibit ectopic axon projections to the hypothalamus and cerebral peduncle. Together, our findings show that Tbr1 coordinately regulates regional and laminar identity of postmitotic cortical neurons.

297 citations

Journal Article•DOI•
Cajal—Retzius cells, Reelin, and the formation of layers

[...]

Michael Frotscher1•
University of Freiburg1
01 Oct 1998-Current Opinion in Neurobiology
TL;DR: Early-generated Cajal-Retzius cells in the marginal zone of the cortex synthesize and secrete the glycoprotein Reelin, and the reelin gene is deleted in reeler mice, which show characteristic alterations in cortical lamination.

276 citations

Journal Article•DOI•
Neuroepithelial stem cell proliferation requires LIS1 for precise spindle orientation and symmetric division

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Jessica Yingling1, Yong Ha Youn1, Dawn L. Darling1, Kazuhito Toyo-oka2, Kazuhito Toyo-oka1, Tiziano Pramparo1, Shinji Hirotsune2, Anthony Wynshaw-Boris1 •
University of California, San Diego1, Osaka City University2
08 Feb 2008-Cell
TL;DR: Control of symmetric division, essential for neuroepithelial stem cell proliferation, is mediated through spindle orientation determined via LIS1/NDEL1/dynein-mediated cortical microtubule capture.

265 citations

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