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.

Human embryonic stem cell-derived cerebral organoids for treatment of mild traumatic brain injury in a mouse model

“…In addition, other important cell types such as microglia and endothelial cells derived from the mesoderm were not present in the COs in previous researches and these features are common limitations of CO research which need to be overcome. 44 Accordingly, it will be necessary to develop hybrid culture systems with various types of cells to generate more complete COs, using highly controlled protocols.…”

Human Brain Organoids in Migraine Research: Pathogenesis and Drug Development

“…The connections among distinct brain regions in migraine pathogenesis can potentially be reproduced in brain assembloids to assist in understanding alterations in the connectivity of neural networks in this disorder. Addressing connectivity in in vitro research might be challenging, but advancements in assembloids can generate a robust model to facilitate translating connectivity measurements that are recorded by neuronal imaging in human brains to possible investigations in human brain organoids [ 123 ]. Advances in bioengineering techniques will most likely help overcome the existing challenges in developing organoids [ 28 ] or assembloids [ 34 ] for migraines.…”

Direct Conversion to Achieve Glial Cell Fates: Oligodendrocytes and Schwann Cells

“…Recently, the establishment of organoids which mimic natural stimuli for tissue development, including cell-cell interactions, are at the forefront of stem cell research. Obtaining functional brain organoids in which mature glial cells are present is an extremely difficult challenge that is drawing considerable attention nowadays within the stem cell field ( 98 ). As mentioned earlier, the limitation of the glial differentiation, which appears late in development, is still not overcome, even in brain organoids.…”