Cell diversity and network dynamics in photosensitive human brain organoids

Quadrato, Giorgia; Nguyen, Tuan; Macosko, Evan Z.; Sherwood, J. L.; Yang, Sung Min; Berger, Daniel R.; Maria, Natalie; Scholvin, Jörg; Goldman, Melissa; Kinney, Justin P.; Boyden, Edward S.; Lichtman, Jeff W.; Williams, Ziv; McCarroll, Steven A.; Arlotta, Paola

doi:10.1038/nature22047

Cited by 1,019 publications

(1,223 citation statements)

References 44 publications

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“…Building on these earlier works, a recent flurry of papers described the generation of various neural organoids (Table 1), ranging from the whole‐brain organoids,27, 28, 29 to large sub‐brain regions such as cortical organoids,30, 31 to specific regions, including cerebellum,32 midbrain,33 adenohypophysis,34 hypothalamus,35 and hippocampus 36. Comparing with the classical neurospheres, these organoids are generally much larger.…”

Section: Brain Organoids: Current Technologiesmentioning

confidence: 99%

“…In addition, even within the same batch of organoids, there is variation among the organoids in terms of the parts of brain represented and their spatial distributions 28. As a result, current methods are most suited to investigate strong or overt phenotypes.…”

Section: Current Limitations Of Brain Organoidsmentioning

confidence: 99%

“…Current brain organoids closely resemble fetal brains,28, 30, 66 and can only partially represent the diverse functional cell types of the brain, making them less ideal for studying complex network activities and circuit formations. It also raises the question as in to what extent can brain organoids effectively model neuropsychiatric or neurodegenerative diseases.…”

Section: Current Limitations Of Brain Organoidsmentioning

confidence: 99%

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Translational potential of human brain organoids

Sun

Tan

2018

Ann Clin Transl Neurol

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The recent technology of 3D cultures of cellular aggregates derived from human stem cells have led to the emergence of tissue‐like structures of various organs including the brain. Brain organoids bear molecular and structural resemblance with developing human brains, and have been demonstrated to recapitulate several physiological and pathological functions of the brain. Here we provide an overview of the development of brain organoids for the clinical community, focusing on the current status of the field with an critical evaluation of its translational value.

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Section: Brain Organoids: Current Technologiesmentioning

confidence: 99%

Section: Current Limitations Of Brain Organoidsmentioning

confidence: 99%

Section: Current Limitations Of Brain Organoidsmentioning

confidence: 99%

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Translational potential of human brain organoids

Sun

Tan

2018

Ann Clin Transl Neurol

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“…Functional neuronal activity has been demonstrated with patch clamp recordings of sliced cerebral organoids (5). Additionally, spontaneous neuronal network activity is beginning to be reported in cerebral organoids using high density silicon microelectrodes (6). Further possibilities of high density multielectrode array analysis may allow for additional characterization of cerebral organoid neural networks in both WT and experimental conditions.…”

Section: Commentarymentioning

confidence: 99%

You Have Brains in Your Head, You Have Organoids in Your Dish, you Can Steer Yourself in any Direction you Wish

Thodeson¹,

Hsieh²

2017

Epilepsy Curr

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An expansion of the cerebral neocortex is thought to be the foundation for the unique intellectual abilities of humans. It has been suggested that an increase in the proliferative potential of neural progenitors (NPs) underlies the expansion of the cortex and its convoluted appearance. Here we show that increasing NP proliferation induces expansion and folding in an in vitro model of human corticogenesis. Deletion of PTEN stimulates proliferation and generates significantly larger and substantially folded cerebral organoids. This genetic modification allows sustained cell cycle reentry, expansion of the progenitor population, and delayed neuronal differentiation, all key features of the developing human cortex. In contrast, Pten deletion in mouse organoids does not lead to folding. Finally, we utilized the expanded cerebral organoids to show that infection with Zika virus impairs cortical growth and folding. Our study provides new insights into the mechanisms regulating the structure and organization of the human cortex. Classical lissencephaly is a genetic neurological disorder associated with mental retardation and intractable epilepsy, and Miller-Dieker syndrome (MDS) is the most severe form of the disease. In this study, to investigate the effects of MDS on human progenitor subtypes that control neuronal output and influence brain topology, we analyzed cerebral organoids derived from control and MDS-induced pluripotent stem cells (iPSCs) using time-lapse imaging, immunostaining, and single-cell RNA sequencing. We saw a cell migration defect that was rescued when we corrected the MDS causative chromosomal deletion and severe apoptosis of the founder neuroepithelial stem cells, accompanied by increased horizontal cell divisions. We also identified a mitotic defect in outer radial glia, a progenitor subtype that is largely absent from lissencephalic rodents but critical for human neocortical expansion. Our study, therefore, deepens our understanding of MDS cellular pathogenesis and highlights the broad utility of cerebral organoids for modeling humanneurodevelopmental disorders. The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (γ-aminobutyric-acid-releasing) neurons from ventral to dorsal forebrain and their integration into cortical circuits. However, these interregional interactions have not yet been modelled with human cells. Here we generate three-dimensional spheroids from human pluripotent stem cells that resemble either the dorsal or ventral forebrain and contain cortical glutamatergic or GABAergic neurons. These subdomain-specific forebrain spheroids can be assembled in vitro to recapitulate the saltatory migration of interneurons observed in the fetal forebrain. Using this system, we find that in Timothy syndrome-a neurodevelopmental disorder that is caused by mutations in the Ca V 1.2 calcium Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia Assembly of F...

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“…Time will tell just how much information these mini-brains can provide. ■ 6 induced PSCs to form a cell layer that self-patterned into organoids composed of multiple brain regions. Measurements of neuronal activity revealed that the organoids contain cells that respond to light in a similar way to photoreceptor cells of the retina, demonstrating that neurons can mature in organoids.…”

mentioning

confidence: 99%

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2017

Nature

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Cell diversity and network dynamics in photosensitive human brain organoids

Cited by 1,019 publications

References 44 publications

Translational potential of human brain organoids

Translational potential of human brain organoids

You Have Brains in Your Head, You Have Organoids in Your Dish, you Can Steer Yourself in any Direction you Wish

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