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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

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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

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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
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Journal Article•DOI•
Cell biological regulation of division fate in vertebrate neuroepithelial cells

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Minde I. Willardsen1, Brian A. Link1•
Medical College of Wisconsin1
01 Aug 2011-Developmental Dynamics
TL;DR: Three key cellular parameters, asymmetric inheritance, cell cycle kinetics, and interkinetic nuclear migration, are reviewed, and the possible mechanisms for how these features influence progenitor fates are reviewed.
Abstract: The developing nervous system derives from neuroepithelial progenitor cells that divide to generate all of the mature neuronal types. For the proper complement of cell types to form, the progenitors must produce postmitotic cells, yet also replenish the progenitor pool. Progenitor divisions can be classified into three general types: symmetric proliferative (producing two progenitors), asymmetric neurogenic (producing one progenitor and one postmitotic cell), and symmetric neurogenic (producing two postmitotic cells). The appropriate ratios for these modes of cell division require intrinsic polarity, which is one of the characteristics that define neuroepithelial progenitor cells. The type of division an individual progenitor undergoes can be influenced by cellular features, or behaviors, which are heterogeneous within the population of progenitors. Here we review three key cellular parameters, asymmetric inheritance, cell cycle kinetics, and interkinetic nuclear migration, and the possible mechanisms for how these features influence progenitor fates.

36 citations

Book Chapter•DOI•
Differentiation of neuroepithelia from human embryonic stem cells.

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Xiaofeng Xia1, Su-Chun Zhang1•
University of Wisconsin-Madison1
01 Jan 2009-Methods of Molecular Biology
TL;DR: The primitive neuroepithelial cells generated by this protocol can be further induced into neuronal and glial cells with forebrain, mid/hind brain, and spinal cord identities and targeted transmitter phenotypes.
Abstract: Neural tissue is derived from the embryonic ectoderm. The initial step in the generation of the vertebrate nervous system is the specification of neuroepithelia from ectodermal cells—a process known as neural induction. The specified neuroepithelia in the midline dorsal ectoderm rapidly grow into a pseudostratified layer of neural plate, which later folds and closes to form the neural tube, the rudiment of the central nervous system (CNS). The lateral lip of the neural plate detaches when the neural plate closes and gives rise to neural crest derivatives. In mouse, neural plate forms at embryonic day 7, whereas in humans, it develops around embryonic day 18 (1).

27 citations

Journal Article•DOI•
Quantitative studies of mitoses in fetal rat brain: orientations of the spindles.

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Stephen Zamenhof1•
University of California, Los Angeles1
01 Jan 1987-Brain Research
TL;DR: Evidence was obtained of ventricular mitoses whose spindles are perpendicular to the surface of the ventricle, suggesting that these perpendicular orientations are not accidental but serve some specific purpose: either they give rise to a different cell population, or they represent a stage preparatory for cell migration.

16 citations

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Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure

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Xuyu Qian, Ha Nam Nguyen, Mingxi M. Song, Christopher Hadiono, Sarah C. Ogden, Christy Hammack, Bing Yao, Gregory R. Hamersky, Fadi Jacob, Chun Zhong, Ki Jun Yoon, William J. Jeang, Li Lin, Yujing Li, Jai Thakor, Daniel A. Berg, Ce Zhang, Eunchai Kang, Michael Chickering, David W. Nauen, Cheng-Ying Ho, Cheng-Ying Ho, Zhexing Wen, Kimberly M. Christian, Pei Yong Shi, Brady J. Maher, Hao Wu, Peng Jin, Hengli Tang, Hongjun Song, Guo Li Ming 
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