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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
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Journal Article•DOI•
Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.

[...]

Kazutoshi Takahashi1, Shinya Yamanaka1•
Kyoto University1
25 Aug 2006-Cell
TL;DR: Induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions is demonstrated and iPS cells, designated iPS, exhibit the morphology and growth properties of ES cells and express ES cell marker genes.

23,959 citations

Journal Article•DOI•
Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche.

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Toshiro Sato1, Robert G.J. Vries1, Hugo J. Snippert1, Marc van de Wetering1, Nick Barker1, Daniel E. Stange1, Johan H. van Es1, Arie Abo, Pekka Kujala2, Peter J. Peters2, Hans Clevers1 •
Utrecht University1, Netherlands Cancer Institute2
14 May 2009-Nature
TL;DR: It is concluded that intestinal crypt–villus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche.
Abstract: The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We have recently demonstrated the presence of about six cycling Lgr5(+) stem cells at the bottoms of small-intestinal crypts. Here we describe the establishment of long-term culture conditions under which single crypts undergo multiple crypt fission events, while simultanously generating villus-like epithelial domains in which all differentiated cell types are present. Single sorted Lgr5(+) stem cells can also initiate these cryptvillus organoids. Tracing experiments indicate that the Lgr5(+) stem-cell hierarchy is maintained in organoids. We conclude that intestinal cryptvillus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche.

5,193 citations

Journal Article•DOI•
Generation of germline-competent induced pluripotent stem cells

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Keisuke Okita1, Tomoko Ichisaka1, Shinya Yamanaka1•
Kyoto University1
19 Jul 2007-Nature
TL;DR: iPS cells competent for germline chimaeras can be obtained from fibroblasts, but retroviral introduction of c-Myc should be avoided for clinical application.
Abstract: We have previously shown that pluripotent stem cells can be induced from mouse fibroblasts by retroviral introduction of Oct3/4 (also called Pou5f1), Sox2, c-Myc and Klf4, and subsequent selection for Fbx15 (also called Fbxo15) expression These induced pluripotent stem (iPS) cells (hereafter called Fbx15 iPS cells) are similar to embryonic stem (ES) cells in morphology, proliferation and teratoma formation; however, they are different with regards to gene expression and DNA methylation patterns, and fail to produce adult chimaeras Here we show that selection for Nanog expression results in germline-competent iPS cells with increased ES-cell-like gene expression and DNA methylation patterns compared with Fbx15 iPS cells The four transgenes (Oct3/4, Sox2, c-myc and Klf4) were strongly silenced in Nanog iPS cells We obtained adult chimaeras from seven Nanog iPS cell clones, with one clone being transmitted through the germ line to the next generation Approximately 20% of the offspring developed tumours attributable to reactivation of the c-myc transgene Thus, iPS cells competent for germline chimaeras can be obtained from fibroblasts, but retroviral introduction of c-Myc should be avoided for clinical application

4,371 citations

Journal Article•DOI•
A ROCK inhibitor permits survival of dissociated human embryonic stem cells

[...]

Kiichi Watanabe1, Morio Ueno, Daisuke Kamiya, Ayaka Nishiyama, Michiru Matsumura, Takafumi Wataya2, Jun Takahashi2, Satomi Nishikawa, Shin-Ichi Nishikawa, Keiko Muguruma, Yoshiki Sasai •
California Institute of Technology1, Kyoto University2
27 May 2007-Nature Biotechnology
TL;DR: Application of a selective Rho-associated kinase (ROCK) inhibitor, Y-27632, to hES cells markedly diminishes dissociation-induced apoptosis, increases cloning efficiency and facilitates subcloning after gene transfer, and enables SFEB-cultured hES Cells to survive and differentiate into Bf1+ cortical and basal telencephalic progenitors.
Abstract: Poor survival of human embryonic stem (hES) cells after cell dissociation is an obstacle to research, hindering manipulations such as subcloning. Here we show that application of a selective Rho-associated kinase (ROCK) inhibitor1,2, Y-27632, to hES cells markedly diminishes dissociation-induced apoptosis, increases cloning efficiency (from ∼1% to ∼27%) and facilitates subcloning after gene transfer. Furthermore, dissociated hES cells treated with Y-27632 are protected from apoptosis even in serum-free suspension (SFEB) culture3 and form floating aggregates. We demonstrate that the protective ability of Y-27632 enables SFEB-cultured hES cells to survive and differentiate into Bf1+ cortical and basal telencephalic progenitors, as do SFEB-cultured mouse ES cells.

2,094 citations

Journal Article•DOI•
The cell biology of neurogenesis.

[...]

Magdalena Götz, Wieland B. Huttner1•
Max Planck Society1
01 Oct 2005-Nature Reviews Molecular Cell Biology
TL;DR: In this paper, the authors discuss how these features change during development from neuroepithelial to radial glial cells, and how this transition affects cell fate and neurogenesis.
Abstract: 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.

1,743 citations

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