Human brain organoids assemble functionally integrated bilateral optic vesicles

Abstract

During embryogenesis, optic vesicles develop from the diencephalon via a complex process of organogenesis. Using iPSC-derived human brain organoids, we attempted to simplify the complexities and demonstrate the formation of forebrain-associated bilateral optic vesicles, cellular diversity, and functionality. Around day thirty, brain organoids could assemble optic vesicles, which progressively develop as visible structures within sixty days. These optic vesicle-containing brain organoids (OVB-Organoids) constitute a developing optic vesicle's cellular components, including the primitive cornea and lens-like cells, developing photoreceptors, retinal pigment epithelia, axon-like projections, and electrically active neuronal networks. Besides, OVB-Organoids also display synapsin-1, CTIP-positive, myelinated cortical neurons, and microglia. Interestingly, various light intensities could trigger photoreceptor activity of OVB-Organoids, and light sensitivities could be reset after a transient photo bleach blinding. Thus, brain organoids have the intrinsic ability to self-organize forebrain-associated primitive sensory structures in a topographically restricted manner and can allow conducting interorgan interaction studies within a single organoid.

A systematic characterization of intrinsically formed microglia-like cells during retinal organoid differentiation

“…This environment and the time frame is similar to when IBA1 + -cells have been reported to appear in human embryonic development (Bloom and Bartelmez, 1940; Kelemen and Jánossa, 1980; Monier et al, 2007; Rezaie et al, 2005). Our results also support a recent study that identified a cluster of microglial cells using RNA-sequencing of brain organoids with bilateral optic vesicles (Gabriel et al, 2021). However, in contrast to human retinal development (Hu et al, 2019), we rarely observed microglia-like cells in the retinal cup at 5 weeks or later ( Supplementary Fig.…”

“…The data regarding intrinsic microglia occurrence are controversial. Whereas single-cell RNA-sequencing of brain organoids with bilateral optic vesicles identified a glial cluster expressing microglia-specific markers (Gabriel et al, 2021), other studies do not report, or the provided data do not support, their presence in retinal organoids (Collin et al, 2019; Cowan et al, 2020; Kim et al, 2019). A microglial transcriptional signature can be detected in human embryonic retinal tissue by gestational week 5 (Hu et al, 2019; Mellough et al, 2019) suggesting that microglia appear early in development.…”

Retina organoids: Window into the biophysics of neuronal systems

“…As the decisive factor between NR and RPE is VSX2, it is widely accepted as an indicator of cells with NR identity in ROs as well. 9,35,[37][38][39][40]46 RPE fate is co-controlled by another TF (MITF) that it is expressed throughout the entire structure in the early optic vesicle. Later on, it is restricted to the RPE.…”

‘Consciousnessoids’: clues and insights from human cerebral organoids for the study of consciousness

“…2017 ). Very recently, optic vesicle-containing brain organoids (OVB) have been grown ( Gabriel et al. 2021 ).…”

“…Importantly, they are light-sensitive, and ‘various light intensities could trigger photosensitive activity of OVB-organoids (...). Thus, brain organoids have the intrinsic ability to self-organize forebrain-associated primitive sensory structures in a topographically restricted manner’ ( Gabriel et al. 2021 ).…”