The Age of Brain Organoids: Tailoring Cell Identity and Functionality for Normal Brain Development and Disease Modeling

Abstract

Over the past years, brain development has been investigated in rodent models, which were particularly relevant to establish the role of specific genes in this process. However, the cytoarchitectonic features, which determine neuronal network formation complexity, are unique to humans. This implies that the developmental program of the human brain and neurological disorders can only partly be reproduced in rodents. Advancement in the study of the human brain surged with cultures of human brain tissue in the lab, generated from induced pluripotent cells reprogrammed from human somatic tissue. These cultures, termed brain organoids, offer an invaluable model for the study of the human brain. Brain organoids reproduce the cytoarchitecture of the cortex and can develop multiple brain regions and cell types. Integration of functional activity of neural cells within brain organoids with genetic, cellular, and morphological data in a comprehensive model for human development and disease is key to advance in the field. Because the functional activity of neural cells within brain organoids relies on cell repertoire and time in culture, here, we review data supporting the gradual formation of complex neural networks in light of cell maturity within brain organoids. In this context, we discuss how the technology behind brain organoids brought advances in understanding neurodevelopmental, pathogen-induced, and neurodegenerative diseases.

Keywords: SARS-CoV-2; Zika virus; brain development; brain organoids; electrophysiology; human pluripotent stem cells (hPSC); neurodegenerative diseases; neurodevelopmental disorders.

Figure 1

Cell types/markers and functional properties reported in brain organoids in a time-dependent fashion, according to the literature. This timeline summarizes the emergence of the main mature cell types in brain organoids from distinct protocols, shown in months. Neurons start to appear in earlier times of culturing (~1 month). Dopaminergic and cholinergic neurons were found enriched in guided protocols. Markers of astrocytes and microglia increase from 1 month, while oligodendrocytes gradually emerge from 3 months of culturing. Early functional properties of developing brains such as giant depolarizing potentials (GDPs)-like can be recorded around 1 month of culture in guided protocols. Electrophysiological maturation such as synchronized burst firing activities, both action and spontaneous inhibitory/excitatory postsynaptic potentials, gradually emerge over time (from 2 months). More complex neural networks resulting from interconnectivity were reported by the presence of periodic oscillatory activity and synaptic plasticity and included long-term potentiation and depression (LTP and LTD) (~5–6 months). Neurons: Glu - glutamatergic; GABA, GABAergic; Dopa, dopaminergic; ACh, cholinergic.

Figure 2

Brain organoids models display hallmarks of neurodevelopmental and neurodegenerative diseases. Time in culture (months) of hallmarks and functional alterations observed in organoids modeling brain disorders are depicted. Neurodevelopmental disorders include microcephaly by viral infection (Zika virus), Autism and Rett's syndrome. Neurodegenerative diseases include Parkinson's and Alzheimer's, and viral infection by SARS-CoV2.