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Neurons Derived from Human Induced Pluripotent Stem Cells Integrate into Rat Brain Circuits and Maintain Both Excitatory and Inhibitory Synaptic Activities.
The human cerebral cortex is a complex structure with tightly interconnected excitatory and inhibitory neuronal networks. In order to study human cortical function, we recently developed a method to generate cortical neurons from human induced pluripotent stem cells (hiPSCs) that form both excitatory and inhibitory neuronal networks resembling the composition of the human cortex. These cultures and organoids recapitulate neuronal populations representative of the six cortical layers and a balanced excitatory and inhibitory network that is functional and homeostatically stable. To determine whether hiPSC-derived neurons can integrate and retain physiologic activities in vivo, we labeled hiPSCs with red fluorescent protein (RFP) and introduced hiPSC-derived neural progenitors to rat brains. Efficient neural induction, followed by differentiation resulted in a RFP+ neural population with traits of forebrain identity and a balanced synaptic activity composed of both excitatory neurons and inhibitory interneurons. Ten weeks after transplantation, grafted cells structurally integrated into the rat forebrain. Remarkably, these hiPSC-derived neurons were able to fire, exhibiting both excitatory and inhibitory postsynaptic currents, which culminates in the establishment of neuronal connectivity with the host circuitry. This study demonstrates that neural progenitors derived from hiPSCs can differentiate into functional cortical neurons and can participate in neural network activity through functional synaptic integration in vivo, thereby contributing to information processing.
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Balancing neuronal activity to fight neurodevelopmental disorders.
In a recent study, Rylaarsdam and colleagues revealed that mutant PACS1 gene, which causes a rare neurodevelopmental syndrome, affects the firing ability of human neurons without dysregulating the cellular architecture of brain organoids. These findings suggest aberrant neuronal electrophysiology as a possible interventional target for pediatric diseases impairing brain development.
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An overview of in vitro 3D models of the blood-brain barrier as a tool to predict the in vivo permeability of nanomedicines.
The blood-brain barrier (BBB) prevents efficient drug delivery to the central nervous system. As a result, brain diseases remain one of the greatest unmet medical needs. Understanding the tridimensional structure of the BBB helps gain insight into the pathology of the BBB and contributes to the development of novel therapies for brain diseases. Therefore, 3D models with an ever-growing sophisticated complexity are being developed to closely mimic the human neurovascular unit. Among these 3D models, hydrogel-, spheroid- and organoid-based static BBB models have been developed, and so have microfluidic-based BBB-on-a-chip models. The different 3D preclinical models of the BBB, both in health and disease, are here reviewed, from their development to their application for permeability testing of nanomedicines across the BBB, discussing the advantages and disadvantages of each model. The validation with data from in vivo preclinical data is also discussed in those cases where provided.
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Unraveling the effects of prenatal anesthesia on neurodevelopment: A review of current evidence and future directions.
Human brain development is a complex, multi-stage, and sensitive process, especially during the fetal stage. Animal studies over the last two decades have highlighted the potential risks of anesthetics to the developing brain, impacting its structure and function. This has raised concerns regarding the safety of anesthesia during pregnancy and its influence on fetal brain development, garnering significant attention from the anesthesiology community. Although preclinical studies predominantly indicate the neurotoxic effects of prenatal anesthesia, these findings cannot be directly extrapolated to humans due to interspecies variations. Clinical research, constrained by ethical and technical hurdles in accessing human prenatal brain tissues, often yields conflicting results compared to preclinical data. The emergence of brain organoids as a cutting-edge research tool shows promise in modeling human brain development. When integrated with single-cell sequencing, these organoids offer insights into potential neurotoxic mechanisms triggered by prenatal anesthesia. Despite several retrospective and cohort studies exploring the clinical impact of anesthesia on brain development, many findings remain inconclusive. As such, this review synthesizes preclinical and clinical evidence on the effects of prenatal anesthesia on fetal brain development and suggests areas for future research advancement.
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Pioneering models of pediatric brain tumors.
Among children and adolescents in the United States (0 to 19 years old), brain and other central nervous system tumors are the second most common types of cancers, surpassed in incidence only by leukemias. Despite significant progress in the diagnosis and treatment modalities, brain cancer remains the leading cause of death in the pediatric population. There is an obvious unfulfilled need to streamline the therapeutic strategies and improve survival for these patients. For that purpose, preclinical models play a pivotal role. Numerous models are currently used in pediatric brain tumor research, including genetically engineered mouse models, patient-derived xenografts and cell lines, and newer models that utilize novel technologies such as genome engineering and organoids. Furthermore, extensive studies by the Children's Brain Tumor Network (CBTN) researchers and others have revealed multiomic landscapes of variable pediatric brain tumors. Combined with such integrative data, these novel technologies have enabled numerous applicable models. Genome engineering, including CRISPR/Cas9, expanded the flexibility of modeling. Models generated through genome engineering enabled studying particular genetic alterations in clean isogenic backgrounds, facilitating the dissection of functional mechanisms of those mutations in tumor biology. Organoids have been applied to study tumor-to-tumor-microenvironment interactions and to address developmental aspects of tumorigenesis, which is essential in some pediatric brain tumors. Other modalities, such as humanized mouse models, could potentially be applied to pediatric brain tumors. In addition to current valuable models, such novel models are anticipated to expedite functional tumor biology study and establish effective therapeutics for pediatric brain tumors.
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Nitric oxide and peroxynitrite as new biomarkers for early diagnosis of autism.
Autism spectrum disorder, or autism, is a neurodevelopmental disorder of the developing child's brain with a genetic causality. It can be diagnosed at about three years after birth when it begins to present itself via a range of neuropsychiatric symptoms. Nitric oxide is a crucial small molecule of life synthesized within cells of our body systems, including cells of our brain. Peroxynitrite is the product of reaction between superoxide anion and nitric oxide. It normally isomerizes into harmless nitrates or nitrites. However, when excessive superoxide anion is present, the cellular concentration of peroxynitrite can increase to a toxic level. Autism has been suggested to cause oxidative damage to brain cells. Until now, it is impossible to sample tissue from a live brain. Instead, stem cells can be derived (from an autism patient's somatic cells) which can then be differentiated and chemically directed to grow into miniature 3-dimensional tissue masses resembling specific brain regions (e.g., the cortex) called brain organoids. This review discusses utilizing nitric oxide and peroxynitrite as biomarkers and comparing their relative concentrations in stem cells and stem cell derived brain organoids of healthy and autistic individuals to develop a bioanalytical process for early diagnosis of autism.
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Commentary on whether progressive brain change underlies the pathology of schizophrenia: Should this even be debated?
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Advanced in vitro models: Microglia in action.
In the central nervous system (CNS), microglia carry out multiple tasks related to brain development, maintenance of brain homeostasis, and function of the CNS. Recent advanced in vitro model systems allow us to perform more detailed and specific analyses of microglial functions in the CNS. The development of human pluripotent stem cells (hPSCs)-based 2D and 3D cell culture methods, particularly advancements in brain organoid models, offers a better platform to dissect microglial function in various contexts. Despite the improvement of these methods, there are still definite restrictions. Understanding their drawbacks and benefits ensures their proper use. In this primer, we review current developments regarding in vitro microglial production and characterization and their use to address fundamental questions about microglial function in healthy and diseased states, and we discuss potential future improvements with a particular emphasis on brain organoid models.
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Beyond the Personhood: An In-Depth Analysis of Moral Considerations in Human Brain Organoid Research.
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Lysosomal dynamics regulate mammalian cortical neurogenesis.
Mammalian neocortex formation follows a stereotypical pattern wherein the self-renew and differentiation of neural stem cells are coordinated with diverse organelle dynamics. However, the role of lysosomes in brain development has long been overlooked. Here, we demonstrate the highly dynamic lysosomal quantities, types, and localizations in developing brain. We observed asymmetric endolysosome inheritance during radial glial cell (RGC) division and the increased autolysosomes within intermediate progenitor cells (IPs) and newborn neurons. Disruption of lysosomal function shortens the S phase of the cell cycle and promotes RGC differentiation. Mechanistically, we revealed a post-transcriptional regulation governing ribosome homeostasis and cell-cycle progression through differential lysosomal activity modulation. In the human forebrain organoid, lysosomal dynamics are conserved; specifically, during the mitosis of outer subventricular zone RGCs (oRGs), lysosomes are inherited by the progeny without basal process. Together, our results identify the critical role of lysosomal dynamics in regulating mouse and human brain development.