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Cerebral organoid

E Sacide Çağlayan
Dual-specificity thyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a strong therapeutic target to ameliorate cognitive functions of Down Syndrome (DS). Genetic normalization of Dyrk1a is sufficient to normalize early cortical developmental phenotypes in DS mouse models. Gyrencephalic human neocortical development is more complex than that in lissencephalic mice, hence cerebral organoids (COs) can be used to model early neurodevelopmental defects of DS. Single copy DYRK1A knockout COs (scDYRK1AKO-COs) can be generated from manipulated DS derived (DS-) induced pluripotent stem cells (iPSCs) and genetic normalization of DYRK1A is expected to result in corrected neurodevelopmental phenotypes that can be reminiscent of normal COs...
October 15, 2016: Cell Biology International
Felipe Mora-Bermúdez, Farhath Badsha, Sabina Kanton, J Gray Camp, Benjamin Vernot, Kathrin Köhler, Birger Voigt, Keisuke Okita, Tomislav Maricic, Zhisong He, Robert Lachmann, Svante Pääbo, Barbara Treutlein, Wieland B Huttner
Human neocortex expansion likely contributed to the remarkable cognitive abilities of humans. This expansion is thought to primarily reflect differences in proliferation versus differentiation of neural progenitors during cortical development. Here, we have searched for such differences by analysing cerebral organoids from human and chimpanzees using immunohistochemistry, live imaging, and single-cell transcriptomics. We find that the cytoarchitecture, cell type composition, and neurogenic gene expression programs of humans and chimpanzees are remarkably similar...
September 26, 2016: ELife
John O Mason, David J Price
The recent development of organoid techniques, in which embryonic brain-like tissue can be grown from human or mouse stem cells in vitro offers the potential to transform the way in which brain development is studied. In this review, we summarise key aspects of the embryonic development of mammalian forebrains, focussing in particular on the cerebral cortex and highlight significant differences between mouse and primates, including human. We discuss recent work using cerebral organoids that has revealed key similarities and differences between their development and that of the brain in vivo...
August 6, 2016: Neuroscience
Lei Wang, Shirui Hou, Young-Goo Han
The unique mental abilities of humans are rooted in the immensely expanded and folded neocortex, which reflects the expansion of neural progenitors, especially basal progenitors including basal radial glia (bRGs) and intermediate progenitor cells (IPCs). We found that constitutively active Sonic hedgehog (Shh) signaling expanded bRGs and IPCs and induced folding in the otherwise smooth mouse neocortex, whereas the loss of Shh signaling decreased the number of bRGs and IPCs and the size of the neocortex. SHH signaling was strongly active in the human fetal neocortex but Shh signaling was not strongly active in the mouse embryonic neocortex, and blocking SHH signaling in human cerebral organoids decreased the number of bRGs...
July 2016: Nature Neuroscience
Beth A Lindborg, John H Brekke, Amanda L Vegoe, Connor B Ulrich, Kerri T Haider, Sandhya Subramaniam, Scott L Venhuizen, Cindy R Eide, Paul J Orchard, Weili Chen, Qi Wang, Francisco Pelaez, Carolyn M Scott, Efrosini Kokkoli, Susan A Keirstead, James R Dutton, Jakub Tolar, Timothy D O'Brien
UNLABELLED: Tissue organoids are a promising technology that may accelerate development of the societal and NIH mandate for precision medicine. Here we describe a robust and simple method for generating cerebral organoids (cOrgs) from human pluripotent stem cells by using a chemically defined hydrogel material and chemically defined culture medium. By using no additional neural induction components, cOrgs appeared on the hydrogel surface within 10-14 days, and under static culture conditions, they attained sizes up to 3 mm in greatest dimension by day 28...
July 2016: Stem Cells Translational Medicine
Jason Dang, Shashi Kant Tiwari, Gianluigi Lichinchi, Yue Qin, Veena S Patil, Alexey M Eroshkin, Tariq M Rana
Emerging evidence from the current outbreak of Zika virus (ZIKV) indicates a strong causal link between Zika and microcephaly. To investigate how ZIKV infection leads to microcephaly, we used human embryonic stem cell-derived cerebral organoids to recapitulate early stage, first trimester fetal brain development. Here we show that a prototype strain of ZIKV, MR766, efficiently infects organoids and causes a decrease in overall organoid size that correlates with the kinetics of viral copy number. The innate immune receptor Toll-like-Receptor 3 (TLR3) was upregulated after ZIKV infection of human organoids and mouse neurospheres and TLR3 inhibition reduced the phenotypic effects of ZIKV infection...
August 4, 2016: Cell Stem Cell
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 Jeang, Li Lin, Yujing Li, Jai Thakor, Daniel A Berg, Ce Zhang, Eunchai Kang, Michael Chickering, David Nauen, 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
Cerebral organoids, three-dimensional cultures that model organogenesis, provide a new platform to investigate human brain development. High cost, variability, and tissue heterogeneity limit their broad applications. Here, we developed a miniaturized spinning bioreactor (SpinΩ) to generate forebrain-specific organoids from human iPSCs. These organoids 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...
May 19, 2016: Cell
Michael A Dyer
Substantial expansion in the number of cerebral cortex neurons is thought to underlie cognitive differences between humans and other primates, although the mechanisms underlying this expansion are unclear. Otani et al. (2016) utilize PSC-derived brain organoids to study how species-specific differences in cortical progenitor proliferation may underlie cortical evolution.
April 7, 2016: Cell Stem Cell
Tomoki Otani, Maria C Marchetto, Fred H Gage, Benjamin D Simons, Frederick J Livesey
Variation in cerebral cortex size and complexity is thought to contribute to differences in cognitive ability between humans and other animals. Here we compare cortical progenitor cell output in humans and three nonhuman primates using directed differentiation of pluripotent stem cells (PSCs) in adherent two-dimensional (2D) and organoid three-dimensional (3D) culture systems. Clonal lineage analysis showed that primate cortical progenitors proliferate for a protracted period of time, during which they generate early-born neurons, in contrast to rodents, where this expansion phase largely ceases before neurogenesis begins...
April 7, 2016: Cell Stem Cell
Tomasz J Nowakowski, Alex A Pollen, Elizabeth Di Lullo, Carmen Sandoval-Espinosa, Marina Bershteyn, Arnold R Kriegstein
The recent outbreak of Zika virus (ZIKV) in Brazil has been linked to substantial increases in fetal abnormalities and microcephaly. However, information about the underlying molecular and cellular mechanisms connecting viral infection to these defects remains limited. In this study we have examined the expression of receptors implicated in cell entry of several enveloped viruses including ZIKV across diverse cell types in the developing brain. Using single-cell RNA-seq and immunohistochemistry, we found that the candidate viral entry receptor AXL is highly expressed by human radial glial cells, astrocytes, endothelial cells, and microglia in developing human cortex and by progenitor cells in developing retina...
May 5, 2016: Cell Stem Cell
Richard J McMurtrey
Diffusion models are important in tissue engineering as they enable an understanding of gas, nutrient, and signaling molecule delivery to cells in cell cultures and tissue constructs. As three-dimensional (3D) tissue constructs become larger, more intricate, and more clinically applicable, it will be essential to understand internal dynamics and signaling molecule concentrations throughout the tissue and whether cells are receiving appropriate nutrient delivery. Diffusion characteristics present a significant limitation in many engineered tissues, particularly for avascular tissues and for cells whose viability, differentiation, or function are affected by concentrations of oxygen and nutrients...
March 2016: Tissue Engineering. Part C, Methods
J Gray Camp, Farhath Badsha, Marta Florio, Sabina Kanton, Tobias Gerber, Michaela Wilsch-Bräuninger, Eric Lewitus, Alex Sykes, Wulf Hevers, Madeline Lancaster, Juergen A Knoblich, Robert Lachmann, Svante Pääbo, Wieland B Huttner, Barbara Treutlein
Cerebral organoids-3D cultures of human cerebral tissue derived from pluripotent stem cells-have emerged as models of human cortical development. However, the extent to which in vitro organoid systems recapitulate neural progenitor cell proliferation and neuronal differentiation programs observed in vivo remains unclear. Here we use single-cell RNA sequencing (scRNA-seq) to dissect and compare cell composition and progenitor-to-neuron lineage relationships in human cerebral organoids and fetal neocortex. Covariation network analysis using the fetal neocortex data reveals known and previously unidentified interactions among genes central to neural progenitor proliferation and neuronal differentiation...
December 22, 2015: Proceedings of the National Academy of Sciences of the United States of America
Debra L Silver
The cerebral cortex controls our most distinguishing higher cognitive functions. Human-specific gene expression differences are abundant in the cerebral cortex, yet we have only begun to understand how these variations impact brain function. This review discusses the current evidence linking non-coding regulatory DNA changes, including enhancers, with neocortical evolution. Functional interrogation using animal models reveals converging roles for our genome in key aspects of cortical development including progenitor cell cycle and neuronal signaling...
February 2016: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
Jasmine M McCammon, Hazel Sive
Mental health disorders are notoriously difficult to diagnose and treat for a variety of reasons, including genetic heterogeneity, comorbidities, and qualitative diagnostic criteria. Discovery of the molecular pathology underlying these disorders is crucial to the development of quantitative biomarkers and novel therapeutics. In this review, we discuss contributions to the mental health field of different cellular and whole-animal approaches in characterizing psychiatric genetics and molecular pathology. These approaches include mammalian cell and neuronal culture, cerebral organoids, induced pluripotent stem cells, and the whole-animal models of nematodes, flies, mollusks, frogs, mice, and zebrafish, on the last of which we place extra emphasis...
2015: Annual Review of Genomics and Human Genetics
Catarina Vicente
Juergen Knoblich is a senior scientist and deputy scientific director of the Institute of Molecular Biotechnology of the Austrian Academy of Sciences in Vienna. We met Juergen at the 56(th) Annual Drosophila Research Conference, where we asked him about his work in this model system and, more recently, on human cerebral organoids, and about his thoughts on recent technological developments and the funding situation.
May 15, 2015: Development
Deniz Belen
No abstract text is available yet for this article.
2014: Turkish Neurosurgery
Madeline A Lancaster, Juergen A Knoblich
Human brain development exhibits several unique aspects, such as increased complexity and expansion of neuronal output, that have proven difficult to study in model organisms. As a result, in vitro approaches to model human brain development and disease are an intense area of research. Here we describe a recently established protocol for generating 3D brain tissue, so-called cerebral organoids, which closely mimics the endogenous developmental program. This method can easily be implemented in a standard tissue culture room and can give rise to developing cerebral cortex, ventral telencephalon, choroid plexus and retinal identities, among others, within 1-2 months...
October 2014: Nature Protocols
Yan Li, Chunhui Xu, Teng Ma
Pluripotent stem cells (PSCs) have the ability to spontaneously generate structured tissues in vitro reminiscent of embryonic tissue development. Recently, complex organoids such as cortical tissues, cerebral brain organoids, optical cups, intestinal tissues, and liver buds have been generated from PSCs derived from healthy individuals and patients with genetic diseases, providing powerful tools to understand morphogenesis and disease pathology. This article highlights recent advances in the state-of-art generation of organoids from PSCs, possible signaling pathways and mechanisms involved in organogenesis, and the understanding of extracellular microenvironment...
April 2014: Organogenesis
Nobutaka Hattori
No abstract text is available yet for this article.
February 2014: Movement Disorders: Official Journal of the Movement Disorder Society
Luca Muzio, G Giacomo Consalez
The recent discovery of a new three-dimensional culture system for the derivation of cerebral organoids from human induced pluripotent stem cells provides developmental neurobiologists with the first example of a three-dimensional framework for the study of human brain development. This innovative approach permits the in vitro assembly of a human embryonic brain rudiment that recapitulates the developing human cerebrum. Organoids contain progenitor populations that develop to yield mature cortical neuron subtypes, potentially allowing investigators to study complex brain diseases that lack appropriate animal models...
2013: Stem Cell Research & Therapy
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