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Nuclear Receptor TLX in Development and Diseases.
The nuclear receptor TLX (NR2E1) is a transcription factor that is critical for neural development and adult neurogenesis through its actions in regulating neural stem cell proliferation, self-renewal, and fate determination. These roles are primarily executed by regulating TLX downstream target genes involved in myriad pathways such as cell cycle progression, RNA processing, angiogenesis, and senescence. Recent studies suggest that dysregulation of TLX pathways plays an important role in the pathogenesis of human neurological disorders and brain tumors. Here, we will highlight recent progress in the roles of TLX in brain development and adult neurogenesis, and the relevance of TLX to neurological diseases and brain tumors. We will also discuss the potential of TLX as a therapeutic target for these disorders.
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3D organoids containing endothelial and neural cells generation by serial inductions of differentiation on human iPSC-derived embryoid bodies.
3D brain organoids have been widely used as a tool to study human brain development and disorders. Although endothelial cells play important roles in the brain development and pathogenesis in neurological disorders, most 3D brain organoids lack inherent endothelial cells and need either the addition of endothelial cells or to be transplanted to animals to reconstitute such vascular structures, likely missing the developmental interactions of endothelial cells and other cells in the human brain. In order to reconstitute a 3D organoid mimicking the in vivo neural and endothelial cells development, we cultured iPSC-derived embryoid bodies in sequentially applied endothelial and neuronal induction media along with Matrigel embedding. The resulting 3D organoid consists of both neural cells and endothelial cells with vascular like structures, as determined by immunostaining. With scRNA-Seq analysis, the brain organoid was confirmed to contain neural cell types similar with human brains, including a variety of excitatory and inhibitory neurons and glia. Furthermore, when compared with traditional cerebral organoids without endothelial cells using RNA-Seq analysis, the endothelial containing neural organoids (EC-neural organoids) showed difference in gene profiles and favored angiogenesis and vasculogenesis. Of the differentially expressed genes, KRBA2 expression was found higher in neural cells and its inhibition by siRNA treatment resulted in decreased transcriptions of a variety of genes such as neuronal differentiation specific genes but not in genes specific to pluripotent stem cells such as OCT4. The EC-neural organoids also express receptors to SARS-CoV-2 similar to human brains. This 3D model provides a useful tool to study the interactions of endothelial cells and neural cells in the brain development and neural infectious disorders where endothelial cells and pericytes play pivotal roles.
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Studying Heterotypic Cell⁻Cell Interactions in the Human Brain Using Pluripotent Stem Cell Models for Neurodegeneration.
Human cerebral organoids derived from induced pluripotent stem cells (iPSCs) provide novel tools for recapitulating the cytoarchitecture of the human brain and for studying biological mechanisms of neurological disorders. However, the heterotypic interactions of neurovascular units, composed of neurons, pericytes (i.e., the tissue resident mesenchymal stromal cells), astrocytes, and brain microvascular endothelial cells, in brain-like tissues are less investigated. In addition, most cortical organoids lack a microglia component, the resident immune cells in the brain. Impairment of the blood-brain barrier caused by improper crosstalk between neural cells and vascular cells is associated with many neurodegenerative disorders. Mesenchymal stem cells (MSCs), with a phenotype overlapping with pericytes, have promotion effects on neurogenesis and angiogenesis, which are mainly attributed to secreted growth factors and extracellular matrices. As the innate macrophages of the central nervous system, microglia regulate neuronal activities and promote neuronal differentiation by secreting neurotrophic factors and pro-/anti-inflammatory molecules. Neuronal-microglia interactions mediated by chemokines signaling can be modulated in vitro for recapitulating microglial activities during neurodegenerative disease progression. In this review, we discussed the cellular interactions and the physiological roles of neural cells with other cell types including endothelial cells and microglia based on iPSC models. The therapeutic roles of MSCs in treating neural degeneration and pathological roles of microglia in neurodegenerative disease progression were also discussed.
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Biology and Models of the Blood-Brain Barrier.
The blood-brain barrier (BBB) is one of the most selective endothelial barriers. An understanding of its cellular, morphological, and biological properties in health and disease is necessary to develop therapeutics that can be transported from blood to brain. In vivo models have provided some insight into these features and transport mechanisms adopted at the brain, yet they have failed as a robust platform for the translation of results into clinical outcomes. In this article, we provide a general overview of major BBB features and describe various models that have been designed to replicate this barrier and neurological pathologies linked with the BBB. We propose several key parameters and design characteristics that can be employed to engineer physiologically relevant models of the blood-brain interface and highlight the need for a consensus in the measurement of fundamental properties of this barrier.
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The sulfation pattern of glycosaminoglycans in human brain development and neurological disorders such as Alzheimer's disease.
Glycosaminoglycans (GAGs) are modified by various sulfotransferases and endosulfatases. The resulting sulfation patterns are formed, influencing numerous functions. Sulfation leads to a strong negative charge on GAGs, inducing specific interactions with proteins such as signaling ligands and pathogenicity factors, impacting cellular functions and disease onset. Although a long history of research has greatly advanced our understanding of GAGs and the sulfation patterns in model organisms, studies of human brain development and the pathogenesis of neurological diseases are in their infancy. To elucidate the role of the sulfation patterns in the human brain, it is necessary to determine the interplay of factors such as core proteins, GAG elongation enzymes, and sulfotransferases in a hierarchical manner. In recent years, technological advances in, for example, genomic mutation analysis, single-cell analysis, and in vitro brain development models, have begun to inform our understanding of the role of the sulfation patterns in human brain development and neurological disorders such as Alzheimer's disease.
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Brain organoids and organoid intelligence from ethical, legal, and social points of view.
Human brain organoids, aka cerebral organoids or earlier "mini-brains", are 3D cellular models that recapitulate aspects of the developing human brain. They show tremendous promise for advancing our understanding of neurodevelopment and neurological disorders. However, the unprecedented ability to model human brain development and function in vitro also raises complex ethical, legal, and social challenges. Organoid Intelligence (OI) describes the ongoing movement to combine such organoids with Artificial Intelligence to establish basic forms of memory and learning. This article discusses key issues regarding the scientific status and prospects of brain organoids and OI, conceptualizations of consciousness and the mind-brain relationship, ethical and legal dimensions, including moral status, human-animal chimeras, informed consent, and governance matters, such as oversight and regulation. A balanced framework is needed to allow vital research while addressing public perceptions and ethical concerns. Interdisciplinary perspectives and proactive engagement among scientists, ethicists, policymakers, and the public can enable responsible translational pathways for organoid technology. A thoughtful, proactive governance framework might be needed to ensure ethically responsible progress in this promising field.
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Lessons from ex vivo and in vitro models in microglia research.
Microglia are resident immune cells of the central nervous system (CNS) that dynamically adapt to their microenvironment to achieve multiple housekeeping roles. While ex vivo and in vitro models are instrumental tools to study microglial function, the slicing or culturing process inherently leads to markedly altered microglial phenotypes. Understanding the nature of these limitations and developing better ex vivo and in vitro models are crucial for enhancing the utility of these methods. In this review, we discuss recent developments in ex vivo and in vitro microglia models, from cell cultures to brain slices, focusing on the mechanisms that may need to be considered when using these tools and interpreting the obtained results. We suggest that limitations of ex vivo and in vitro models also provide opportunities to better understand the mechanisms driving microglial phenotype changes in various disease states.
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Regulation of melanocortin-4-receptor (MC4R) expression by SNP rs17066842 is dependent on glucose concentration.
Melanocortin-4-receptor (MC4R) gene codes for a G-protein-coupled receptor that is highly expressed in the hypothalamus and involved in the regulation of appetite. Single-nucleotide polymorphisms (SNPs) in the MC4R gene region have been associated with obesity, type 2-diabetes (T2D) and with antipsychotic-induced weight gain. Of these, rs17066842 (G>A) in the MC4R promoter region is the top variant associated with obesity and diabetes. In this study, we investigated the effect of rs17066842 on MC4R expression at various glucose concentrations using reporter gene expression in the SH-SY5Y cell line and regulation of MC4R expression in human cerebral organoids. We observed that higher glucose concentrations significantly reduced MC4R mRNA expression in SH-SY5Y cells. In addition, at high glucose concentrations, the luciferase reporter plasmid containing the MC4R promoter insert with the G-allele of rs170066842 showed significantly reduced activity compared to the A-allele carrying plasmid. The immediate early gene product, early growth-response 1 (EGR-1), was identified to bind to the sequence containing the G-allele at rs17066842 but not to the A-allele-containing sequence. Interestingly, in human induced pluripotent stem cell (hiPSC)-derived cerebral organoids, we observed increased MC4R expression in response to high glucose exposure. These opposite observations might suggest that glucose regulation is complex and may be cell-specific. This study provides evidence that rs17066842 regulates MC4R gene expression through binding of EGR-1 and that this process is influenced by glucose concentration.
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Harnessing Intelligence from Brain Cells In Vitro.
Harnessing intelligence from brain cells in vitro requires a multidisciplinary approach integrating wetware, hardware, and software. Wetware comprises the in vitro brain cells themselves, where differentiation from induced pluripotent stem cells offers ethical scalability; hardware typically involves a life support system and a setup to record the activity from and deliver stimulation to the brain cells; and software is required to control the hardware and process the signals coming from and going to the brain cells. This review provides a broad summary of the foundational technologies underpinning these components, along with outlining the importance of technology integration. Of particular importance is that this new technology offers the ability to extend beyond traditional methods that assess primarily the survival and spontaneous activity of neural cultures. Instead, the focus returns to the core function of neural tissue: the neurocomputational ability to process information and respond accordingly. Therefore, this review also covers work that, despite the relatively early state of current technology, has provided novel and meaningful understandings in the field of neuroscience along with opening exciting avenues for future research.
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Microfluidic and Computational Tools for Neurodegeneration Studies.
Understanding the molecular, cellular, and physiological components of neurodegenerative diseases (NDs) is paramount for developing accurate diagnostics and efficacious therapies. However, the complexity of ND pathology and the limitations associated with conventional analytical methods undermine research. Fortunately, microfluidic technology can facilitate discoveries through improved biomarker quantification, brain organoid culture, and small animal model manipulation. Because this technology can increase experimental throughput and the number of metrics that can be studied in concert, it demands more sophisticated computational tools to process and analyze results. Advanced analytical algorithms and machine learning platforms can address this challenge in data generated from microfluidic systems, but they can also be used outside of devices to discern patterns in genomic, proteomic, anatomical, and cognitive data sets. We discuss these approaches and their potential to expedite research discoveries and improve clinical outcomes through ND characterization, diagnosis, and treatment platforms.