Sliced Human Cortical Organoids for Modeling Distinct Cortical Layer Formation

Qian, Xuyu; Su, Yijing; Adam, Christopher D.; Deutschmann, André U.; Pather, Sarshan R.; Goldberg, Ethan M.; Su, Kenong; Li, Shiying; Lu, Lu; Jacob, Fadi; Nguyen, Phuong; Huh, Sooyoung; Höke, Ahmet; Swinford-Jackson, Sarah E.; Wen, Zhexing; Gu, Xiaosong; Pierce, R. Christopher; Wu, Hao; Briand, Lisa A.; Chen, H. Isaac; Wolf, John A.; Song, Hongjun; Guo, Ming

doi:10.1016/j.stem.2020.02.002

Cited by 340 publications

(335 citation statements)

References 73 publications

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“…The generation of cerebral organoid is a highly dynamic model of the embryonic developing brain over time 103 . Notably, cerebral organoids closely resemble neurons in the cortex and choroid plexus 36,70,104 . Our organoids exhibited similar developmental patterns, contained multiple brain cell types (e.g., NSCs, neurons, and astrocytes), and showed distinct multi-layered, cortical-like neuronal zone and choroid plexus (Fig.…”

Section: Discussionmentioning

confidence: 99%

Modeling alcohol-induced neurotoxicity using human induced pluripotent stem cell-derived three-dimensional cerebral organoids

et al. 2020

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Maternal alcohol exposure during pregnancy can substantially impact the development of the fetus, causing a range of symptoms, known as fetal alcohol spectrum disorders (FASDs), such as cognitive dysfunction and psychiatric disorders, with the pathophysiology and mechanisms largely unknown. Recently developed human cerebral organoids from induced pluripotent stem cells are similar to fetal brains in the aspects of development and structure. These models allow more relevant in vitro systems to be developed for studying FASDs than animal models. Modeling binge drinking using human cerebral organoids, we sought to quantify the downstream toxic effects of alcohol (ethanol) on neural pathology phenotypes and signaling pathways within the organoids. The results revealed that alcohol exposure resulted in unhealthy organoids at cellular, subcellular, bioenergetic metabolism, and gene expression levels. Alcohol induced apoptosis on organoids. The apoptotic effects of alcohol on the organoids depended on the alcohol concentration and varied between cell types. Specifically, neurons were more vulnerable to alcohol-induced apoptosis than astrocytes. The alcohol-treated organoids exhibit ultrastructural changes such as disruption of mitochondria cristae, decreased intensity of mitochondrial matrix, and disorganized cytoskeleton. Alcohol exposure also resulted in mitochondrial dysfunction and metabolic stress in the organoids as evidenced by (1) decreased mitochondrial oxygen consumption rates being linked to basal respiration, ATP production, proton leak, maximal respiration and spare respiratory capacity, and (2) increase of non-mitochondrial respiration in alcohol-treated organoids compared with control groups. Furthermore, we found that alcohol treatment affected the expression of 199 genes out of 17,195 genes analyzed. Bioinformatic analyses showed the association of these dysregulated genes with 37 pathways related to clinically relevant pathologies such as psychiatric disorders, behavior, nervous system development and function, organismal injury and abnormalities, and cellular development. Notably, 187 of these genes are critically involved in neurodevelopment, and/or implicated in nervous system physiology and neurodegeneration. Furthermore, the identified genes are key regulators of multiple pathways linked in networks. This study extends for the first time animal models of binge drinking-related FASDs to a human model, allowing in-depth analyses of neurotoxicity at tissue, cellular, subcellular, metabolism, and gene levels. Hereby, we provide novel insights into alcohol-induced pathologic phenotypes, cell type-specific vulnerability, and affected signaling pathways and molecular networks, that can contribute to a better understanding of the developmental neurotoxic effects of binge drinking during pregnancy.

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Section: Discussionmentioning

confidence: 99%

Modeling alcohol-induced neurotoxicity using human induced pluripotent stem cell-derived three-dimensional cerebral organoids

et al. 2020

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“…However, the use of non-adherent organoids has bene ts at the practical level, as a major risk to long-term 2D cultures is the spontaneous detachment from cell culture plates. Further, the technology is continually evolving, for example through the development of vascularised organoids (41,42) and slice cultures which enable the formation of distinct cortical layers (43). Thus, further acceleration of organoid maturity is likely to be possible in the future.…”

Section: Discussionmentioning

confidence: 99%

Engineered Cerebral Organoids Recapitulate Adult Tau Expression and Disease-relevant Changes in Tau Splicing

Lovejoy

Alatza

Arber

et al. 2020

Preprint

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The tauopathies are a collection of clinically and pathologically diverse neurodegenerative disorders characterised by tau pathology. The tau protein exists as multiple protein isoforms in the adult human CNS, generated by alternative splicing of the MAPT gene. Disruptions to tau splicing are associated with a number of tauopathies, however, in vitro and in vivo models to understand the consequences of disrupted tau splicing have been lacking, due in part to species differences in tau splicing and the developmental regulation of tau in human neurons. We investigated the utility of iPSC-derived cerebral organoids to model key aspects of tau biology. Cerebral organoids showed high variability in neuronal content and tau expression. To reduce this heterogeneity, we generated engineered cerebral organoids (enCORs), which use a floating scaffold to increase the efficiency of neural induction and reduce heterogeneity. We show that enCORs provide a robust and reproducible in vitro system for the analysis of tau expression and splicing in a 3D model. To investigate the effect of tau mutations, we generated enCORs from an isogenic series of iPSC with the MAPT 10+16 and P301S mutations. The presence of tau splicing mutations results in disease-associated alterations in tau expression, specifically a dose-dependent increase in 4R tau isoforms in the presence of the MAPT 10+16 variant. While the developmental regulation of tau splicing is conserved, maturation of tau splicing is accelerated in 3D cultures compared to 2D cultures. Finally, enCORs with coding mutations in MAPT are able to produce seed-competent tau species, suggesting enCORs recapitulate early features of tau pathology. In summary, enCORs provide a novel, robust in vitro system for the study of tau in development and disease.

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“…In 2019, Lancaster's group has adopted air-liquid interface culture techniques, which improve the survival rate of neurons and the growth of axons and promotes the formation of circuits and the output of functional neurons (Giandomenico et al, 2019). More recently, it has been found that sliced neocortical organoid system can promote the continuous neurogenesis and dilation of the cortical plate; the cortical plate has distinct upper and deep cortical layers, which captures the neocortex in late human pregnancy and eliminates the restriction of growth and diffusion of brain organoids to some extent (Qian et al, 2020). These results indicate that brain organoids sliced culture can be used to study human-specific advanced cortical development and disease-related mechanisms (Figure 1).…”

Section: Sliced Brain Organoid Culturementioning

confidence: 99%

The Application of Brain Organoids: From Neuronal Development to Neurological Diseases

Shou

Liang

et al. 2020

Front. Cell Dev. Biol.

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Brain organoids are derived from induced pluripotent stem cells and embryonic stem cells under three-dimensional culture condition. The generation of an organoid requires the self-assembly of stem cells, progenitor cells, and multiple types of differentiated cells. Organoids display structures that resemble defined brain regions and simulate specific changes of neurological disorders; thus, organoids have become an excellent model for investigating brain development and neurological diseases. In the present review, we have summarized recent advances of the methods of culturing brain organoids and the applications of brain organoids in investigating neurodevelopmental and neurodegenerative diseases.

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Sliced Human Cortical Organoids for Modeling Distinct Cortical Layer Formation

Abstract: Highlights d SNOs maintain growth and laminar expansion over long-term culture d SNOs exhibit separated upper and deep cortical layers d Layer-specific WNT/b-catenin signaling regulates neuronal fate specification d DISC1 mutation causes deficits in cortical neuron fate specification

Cited by 340 publications

References 73 publications

Modeling alcohol-induced neurotoxicity using human induced pluripotent stem cell-derived three-dimensional cerebral organoids

Modeling alcohol-induced neurotoxicity using human induced pluripotent stem cell-derived three-dimensional cerebral organoids

Engineered Cerebral Organoids Recapitulate Adult Tau Expression and Disease-relevant Changes in Tau Splicing

The Application of Brain Organoids: From Neuronal Development to Neurological Diseases

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