Human brain development through the lens of cerebral organoid models

Abstract

The brain is one of the most complex organs in the body, which emerges from a relatively simple set of basic 'building blocks' during early development according to complex cellular and molecular events orchestrated through a set of inherited instructions. Innovations in stem cell technologies have enabled modelling of neural cells using two- and three-dimensional cultures. In particular, cerebral ('brain') organoids have taken the center stage of brain development models that have the potential for providing meaningful insight into human neurodevelopmental and neurological disorders. We review the current understanding of cellular events during human brain organogenesis, and the events occurring during cerebral organoid differentiation. We highlight the strengths and weaknesses of this experimental model system. In particular, we explain evidence that organoids can mimic many aspects of early neural development, including neural induction, patterning, and broad neurogenesis and gliogenesis programs, offering the opportunity to study genetic regulation of these processes in a human context. Several shortcomings of the current culture methods limit the utility of cerebral organoids to spontaneously give rise to many important cell types, and to model higher order features of tissue organization. We suggest that future studies aim to improve these features in order to make them better models for the study of laminar organization, circuit formation and how disruptions of these processes relate to disease.

Keywords: Brain organoids; Neural development.

Figure 1:. Neural development

A) During early development, notochord cells induce neuroepithelial identity of the overlying epithelium. After neural induction, the neural plate invaginates and closes to form the neural tube. The notochord becomes patterned along the rostral/caudal axis. B) Organizers within the nervous system arise and secrete morphogens to pattern neural tissue resulting in the expression of discrete transcription factor domains. These domains develop into distinct regions of the nervous system. C) Brain organoid protocols co-opt these developmental signals to pattern the cells toward particular identities in an attempt to recapitulate early neurodevelopmental events.

Figure 2:. Cortical Development and organoid models

A) During cortical development radial glia arise from a neuroepithelial sheet. Progenitor cells generate deep layer neurons first before producing upper layer neurons, which expand the cortex. B) In the cortical organoid, cell types can also be identified using the expression of canonical markers. Organoid cells self-organize typically into multiple progenitor zone-like rosette structures, rather than into a single germinal zone as in vivo. Although the VZ-like structure expands, it does not maintain the same cytoarchitectural organization over time. After a period of culturing, a mix of neuronal populations reside on the exterior of the organoid.