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iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer.
Microglia are specialized brain-resident macrophages that arise from primitive macrophages colonizing the embryonic brain1. Microglia contribute to multiple aspects of brain development, but their precise roles in the early human brain remain poorly understood owing to limited access to relevant tissues2-6. The generation of brain organoids from human induced pluripotent stem cells recapitulates some key features of human embryonic brain development7-10. However, current approaches do not incorporate microglia or address their role in organoid maturation11-21. Here we generated microglia-sufficient brain organoids by coculturing brain organoids with primitive-like macrophages generated from the same human induced pluripotent stem cells (iMac)22. In organoid cocultures, iMac differentiated into cells with microglia-like phenotypes and functions (iMicro) and modulated neuronal progenitor cell (NPC) differentiation, limiting NPC proliferation and promoting axonogenesis. Mechanistically, iMicro contained high levels of PLIN2+ lipid droplets that exported cholesterol and its esters, which were taken up by NPCs in the organoids. We also detected PLIN2+ lipid droplet-loaded microglia in mouse and human embryonic brains. Overall, our approach substantially advances current human brain organoid approaches by incorporating microglial cells, as illustrated by the discovery of a key pathway of lipid-mediated crosstalk between microglia and NPCs that leads to improved neurogenesis.
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Taming human brain organoids one cell at a time.
Human brain organoids are self-organizing three-dimensional structures that emerge from human pluripotent stem cells and mimic aspects of the cellular composition and functionality of the developing human brain. Despite their impressive self-organizing capacity, organoids lack the stereotypic structural anatomy of their in vivo counterpart, making conventional analysis techniques underpowered to assess cellular composition and gene network regulation in organoids. Advances in single cell transcriptomics have recently allowed characterization and improvement of organoid protocols, as they continue to evolve, by enabling identification of cell types and states along with their developmental origins. In this review, we summarize recent approaches, progresses and challenges in resolving brain organoid's complexity through single-cell transcriptomics. We then discuss emerging technologies that may complement single-cell RNA sequencing by providing additional readouts of cellular states to generate an organ-level view of developmental processes. Altogether, these integrative technologies will allow monitoring of global gene regulation in thousands of individual cells and will offer an unprecedented opportunity to investigate features of human brain development and disease across multiple cellular modalities and with cell-type resolution.
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Recent Development of Brain Organoids for Biomedical Application.
Over the years, scientists have studied the behavior and anatomy of many animals to understand the own species. However, despite the continuous efforts, it is often difficult to know for certain how the brain works due to the differences between the brains of animals and the human brain. While the use of animal models for research continues, the origin of human cognition and neurological disorders needs further elucidation. To that end, in vitro organoids that exhibit in vivo characteristics of the human brain have been recently developed. These brain-like organoids enable researchers to dive deeper into understanding the human brain, its neurological structures, and the causes of neurological pathologies. This paper reviews the recent developments in the regeneration of brain-like organoids using Matrigel and other alternatives. Further, gel-free methods that may enhance the regeneration process of organoids are discussed. Finally, the vascularized brain organoid growth and development in both in vitro and in vivo conditions are detailed.
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Fusion of Regionally Specified hPSC-Derived Organoids Models Human Brain Development and Interneuron Migration.
Organoid techniques provide unique platforms to model brain development and neurological disorders. Whereas several methods for recapitulating corticogenesis have been described, a system modeling human medial ganglionic eminence (MGE) development, a critical ventral brain domain producing cortical interneurons and related lineages, has been lacking until recently. Here, we describe the generation of MGE and cortex-specific organoids from human pluripotent stem cells that recapitulate the development of MGE and cortex domains, respectively. Population and single-cell RNA sequencing (RNA-seq) profiling combined with bulk assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) analyses revealed transcriptional and chromatin accessibility dynamics and lineage relationships during MGE and cortical organoid development. Furthermore, MGE and cortical organoids generated physiologically functional neurons and neuronal networks. Finally, fusing region-specific organoids followed by live imaging enabled analysis of human interneuron migration and integration. Together, our study provides a platform for generating domain-specific brain organoids and modeling human interneuron migration and offers deeper insight into molecular dynamics during human brain development.
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3D Brain Organoids: Studying Brain Development and Disease Outside the Embryo.
Scientists have been fascinated by the human brain for centuries, yet knowledge of the cellular and molecular events that build the human brain during embryogenesis and of how abnormalities in this process lead to neurological disease remains very superficial. In particular, the lack of experimental models for a process that largely occurs during human in utero development, and is therefore poorly accessible for study, has hindered progress in mechanistic understanding. Advances in stem cell-derived models of human organogenesis, in the form of three-dimensional organoid cultures, and transformative new analytic technologies have opened new experimental pathways for investigation of aspects of development, evolution, and pathology of the human brain. Here, we consider the biology of brain organoids, compared and contrasted with the endogenous human brain, and highlight experimental strategies to use organoids to pioneer new understanding of human brain pathology.
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The Promise and Potential of Brain Organoids.
Brain organoids are 3D in vitro culture systems derived from human pluripotent stem cells that self-organize to model features of the (developing) human brain. This review examines the techniques behind organoid generation, their current and potential applications, and future directions for the field. Brain organoids possess complex architecture containing various neural cell types, synapses, and myelination. They have been utilized for toxicology testing, disease modeling, infection studies, personalized medicine, and gene-environment interaction studies. An emerging concept termed Organoid Intelligence (OI) combines organoids with artificial intelligence systems to generate learning and memory, with the goals of modeling cognition and enabling biological computing applications. Brain organoids allow neuroscience studies not previously achievable with traditional techniques, and have the potential to transform disease modeling, drug development, and the understanding of human brain development and disorders. The aspirational vision of OI parallels the origins of artificial intelligence, and efforts are underway to map a roadmap toward its realization. In summary, brain organoids constitute a disruptive technology that is rapidly advancing and gaining traction across multiple disciplines.
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Applications of Human Brain Organoids to Clinical Problems.
Brain organoids are an exciting new technology with the potential to significantly change how diseases of the brain are understood and treated. These three-dimensional neural tissues are derived from the self-organization of pluripotent stem cells, and they recapitulate the developmental process of the human brain, including progenitor zones and rudimentary cortical layers. Brain organoids have been valuable in investigating different aspects of developmental neurobiology and comparative biology. Several characteristics of organoids also make them attractive as models of brain disorders. Data generated from human organoids are more generalizable to patients because of the match in species background. Personalized organoids also can be generated from patient-derived induced pluripotent stem cells. Furthermore, the three-dimensionality of brain organoids supports cellular, mechanical, and topographical cues that are lacking in planar systems. In this review, we discuss the translational potential of brain organoids, using the examples of Zika virus, autism-spectrum disorder, and glioblastoma multiforme to consider how they could contribute to disease modeling, personalized medicine, and testing of therapeutics. We then discuss areas of improvement in organoid technology that will enhance the translational potential of brain organoids, as well as the possibility of their use as substrates for repairing cerebral circuitry after injury. Developmental Dynamics 248:53-64, 2019. © 2018 Wiley Periodicals, Inc.
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Patterning of brain organoids derived from human pluripotent stem cells.
The emerging technology of brain organoids deriving from human pluripotent stem cells provides unprecedented opportunities to study human brain development and associated disorders. Various brain organoid protocols have been developed that can recapitulate some key features of cell type diversity, cytoarchitectural organization, developmental processes, functions, and pathologies of the developing human brain. In this review, we focus on patterning of human stem cell-derived brain organoids. We start with an overview of general procedures to generate brain organoids. We then highlight some recently developed brain organoid protocols and chemical cues involved in modeling development of specific human brain regions, subregions, and multiple regions together. We also discuss limitations and potential future improvements of human brain organoid technology.
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Brain Organoids and the Study of Neurodevelopment.
Brain organoids are 3D self-assembled structures composed of hundreds of thousands to millions of cells that resemble the cellular organization and transcriptional and epigenetic signature of a developing human brain. Advancements using brain organoids have been made to elucidate the genetic basis of certain neurodevelopmental disorders, such as microcephaly and autism; and to investigate the impact of environmental factors to the brain, such as during Zika virus infection. It remains to be explored how far brain organoids can functionally mature and process external information. An improved brain organoid model might reproduce important aspects of the human brain in a more reproducible and high-throughput fashion. This novel and complementary approach in the neuroscience toolbox opens perspectives to understand the fundamental features of the human neurodevelopment, with implications to personalize therapeutic opportunities for neurological disorders.
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Advances and Applications of Brain Organoids.
Understanding the fundamental processes of human brain development and diseases is of great importance for our health. However, existing research models such as non-human primate and mouse models remain limited due to their developmental discrepancies compared with humans. Over the past years, an emerging model, the "brain organoid" integrated from human pluripotent stem cells, has been developed to mimic developmental processes of the human brain and disease-associated phenotypes to some extent, making it possible to better understand the complex structures and functions of the human brain. In this review, we summarize recent advances in brain organoid technologies and their applications in brain development and diseases, including neurodevelopmental, neurodegenerative, psychiatric diseases, and brain tumors. Finally, we also discuss current limitations and the potential of brain organoids.