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Microplastics exposure affects neural development of human pluripotent stem cell-derived cortical spheroids.
Plastics have been part of our ecosystem for about a century and their degradation by different environmental factors produce secondary microplastics (MPs). To date, the impact of MPs on human health has not been well investigated. To understand the possible effects of polystyrene-MPs (PS-MPs) on the human brain, a 3D model of human forebrain cortical spheroids has been derived, which mimics early development of human cerebral cortex. The spheroids were exposed to 100, 50, and 5 µg/mL of 1 µm and 10 µm PS-MPs during day 4-10 and day 4-30. The short-term MP exposure showed the promoted proliferation and high gene expression of Nestin, PAX6, ATF4, HOXB4 and SOD2. For long-term exposure, reduced cell viability was observed. Moreover, changes in size and concentration of PS-MPs altered the gene expression of DNA damage and neural tissue patterning. In particular, β-tubulin III, Nestin, and TBR1/TBR2 gene expression decreased in PS-MP treated conditions compare to the untreated control. The results of this study suggest that the size- and concentration-dependent exposure to PS-MPs can adversely affect embryonic brain-like tissue development in forebrain cerebral spheroids. This study has significance in assessing environmental factors in neurotoxicity and degeneration in human.
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Individual Peculiarities of the Development and Differentiation of Embryonic Neocortex Transplants in Intact Adult Mouse Brain.
We studied individual peculiarities of the development and differentiation of allogeneic transplants of neocortical cells isolated from embryos at different stages of development in intact brain of adult mice. Despite standard transplantation technique, intraparenchymal grafts considerably varied in size, morphology, and structural organization. The cells in the transplants developing inside the brain ventricles of the recipient formed histotypical structures resembling organoids. Transplants of each age group (12.5, 14.5, and 19.5 days) demonstrated individual peculiarities of cell migration, differentiation, and fiber growth. Only from cells of 12.5-day transplants formed spiny pyramidal neurons typical of V layer of the cerebral cortex. Differentiation of catecholaminergic neurons untypical of brain cortex was observed only in 14.5-day transplants. In few transplants of each age group, extensive cell migration from the transplant was observed. In some transplants, dense astrocyte accumulation was seen. In all cases (n=52), the response of the recipient's glia to the transplant was observed, but formation of an extensive glial barrier was noted only in one case. Our findings suggest that the entire range of the results determined by individual peculiarities of the transplant growth and recipient's response should be thoroughly realized when introducing the methods of neurotransplantation into regenerative medicine.
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Granulin loss of function in human mature brain organoids implicates astrocytes in TDP-43 pathology.
Loss of function (LoF) of TAR-DNA binding protein 43 (TDP-43) and mis-localization, together with TDP-43-positive and hyperphosphorylated inclusions, are found in post-mortem tissue of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those carrying LoF variants in the progranulin gene (GRN). Modeling TDP-43 pathology has been challenging in vivo and in vitro. We present a three-dimensional induced pluripotent stem cell (iPSC)-derived paradigm-mature brain organoids (mbOrg)-composed of cortical-like-astrocytes (iA) and neurons. When devoid of GRN, mbOrgs spontaneously recapitulate TDP-43 mis-localization, hyperphosphorylation, and LoF phenotypes. Mixing and matching genotypes in mbOrgs showed that GRN-/- iA are drivers for TDP-43 pathology. Finally, we rescued TDP-43 LoF by adding exogenous progranulin, demonstrating a link between TDP-43 LoF and progranulin expression. In conclusion, we present an iPSC-derived platform that shows striking features of human TDP-43 proteinopathy and provides a tool for the mechanistic modeling of TDP-43 pathology and patient-tailored therapeutic screening for FTD and ALS.
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Development of Neural Cells and Spontaneous Neural Activities in Engineered Brain-Like Constructs for Transplantation.
Stem cell transplantation has demonstrated efficacy in treating neurological disorders by generating functional cells and secreting beneficial factors. However, challenges remain for current cell suspension injection therapy, including uncontrollable cell distribution, the potential for tumor formation, and limited ability to treat spatial defects. Therefore, implants with programmable cell development, tailored 3D structure, and functionalized biomaterials have the potential to both control cell distribution and reduce or heal spatial defects. Here, a biomimetic material system comprising gelatin, alginate, and fibrinogen has been developed for neural progenitor cell constructs using 3D printing. The resulting constructs exhibit excellent formability, stability, and developmental functions in vitro, as well as biocompatibility and integration into the hippocampus in vivo. The controllability, reproducibility, and material composition of the constructs show potential for use in personalized stem cell-based therapies for defective neurological disorders, neural development research, disease modeling, and organoid-derived intelligent systems.
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A Human Stem Cell-Derived Brain-Liver Chip for Assessing Blood-Brain-Barrier Permeation of Pharmaceutical Drugs.
Significant advancements in the field of preclinical in vitro blood-brain barrier (BBB) models have been achieved in recent years, by developing monolayer-based culture systems towards complex multi-cellular assays. The coupling of those models with other relevant organoid systems to integrate the investigation of blood-brain barrier permeation in the larger picture of drug distribution and metabolization is still missing. Here, we report for the first time the combination of a human induced pluripotent stem cell (hiPSC)-derived blood-brain barrier model with a cortical brain and a liver spheroid model from the same donor in a closed microfluidic system (MPS). The two model compounds atenolol and propranolol were used to measure permeation at the blood-brain barrier and to assess metabolization. Both substances showed an in vivo-like permeation behavior and were metabolized in vitro. Therefore, the novel multi-organ system enabled not only the measurement of parent compound concentrations but also of metabolite distribution at the blood-brain barrier.
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ELAVL Proteins, miRNA Fate, and Extracellular RNA Communication in Brain Aging and Neurodegeneration.
Brain aging is accompanied by changes in RNA homeostasis, intercellular communication, and stress responses that increase vulnerability to neurodegenerative diseases. The neuronal protein HuD (ELAVL4) and the broadly expressed HuR (ELAVL1) regulate RNA stability, translation, localization, and selected microRNA (miRNA) activities. Recent studies further show that HuD can promote export of let-7a and miR-125b during differentiation of PC12 cells, whereas HuR can bind selected miRNAs and engage endosomal export or intracellular buffering mechanisms in other cellular contexts. These observations support an emerging ELAVL-miRNA-extracellular vesicle (EV) framework. They do not yet establish an integrated HuD/HuR-dependent neuron-glia pathway in aging human brain or Alzheimer's disease (AD). We therefore distinguish direct, model-specific findings from hypotheses that age-, amyloid-, or inflammation-associated changes in ELAVL abundance, localization, or RNA binding could redistribute miRNAs between intracellular pools and EVs. Testing this framework in primary human neural cells, induced pluripotent stem cell-derived systems, organoids, and in vivo models may identify context-specific mechanisms and therapeutic opportunities.
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Emerging Application of Nanorobotics and Artificial Intelligence To Cross the BBB: Advances in Design, Controlled Maneuvering, and Targeting of the Barriers.
The blood-brain barrier (BBB) is a prime focus for clinicians to maintain the homeostatic function in health and deliver the theranostics in brain cancer and number of neurological diseases. The structural hierarchy and in situ biochemical signaling of BBB neurovascular unit have been primary targets to recapitulate into the in vitro modules. The microengineered perfusion systems and development in 3D cellular and organoid culture have given a major thrust to BBB research for neuropharmacology. In this review, we focus on revisiting the nanoparticles based bimolecular engineering to enable them to maneuver, control, target, and deliver the theranostic payloads across cellular BBB as nanorobots or nanobots. Subsequently we provide a brief outline of specific case studies addressing the payload delivery in brain tumor and neurological disorders (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, etc.). In addition, we also address the opportunities and challenges across the nanorobots' development and design. Finally, we address how computationally powered machine learning (ML) tools and artificial intelligence (AI) can be partnered with robotics to predict and design the next generation nanorobots to interact and deliver across the BBB without causing damage, toxicity, or malfunctions. The content of this review could be references to multidisciplinary science to clinicians, roboticists, chemists, and bioengineers involved in cutting-edge pharmaceutical design and BBB research.
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Miniaturization of Smart-seq2 for Single-Cell and Single-Nucleus RNA Sequencing.
This protocol presents a plate-based workflow to perform RNA sequencing analysis of single cells/nuclei using Smart-seq2. We describe (1) the dissociation procedures for cell/nucleus isolation from the mouse brain and human organoids, (2) the flow sorting of single cells/nuclei into 384-well plates, and (3) the preparation of libraries following miniaturization of the Smart-seq2 protocol using a liquid-handling robot. This pipeline allows for the reliable, high-throughput, and cost-effective preparation of mouse and human samples for full-length deep single-cell/nucleus RNA sequencing. For complete details on the use and execution of this protocol, please refer to Bowers et al. (2020).
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Cajal-retzius cells: Recent advances in identity and function.
Cajal-Retzius cells (CRs) are a transient neuronal type of the developing cerebral cortex. Over the years, they have been shown or proposed to play important functions in neocortical and hippocampal morphogenesis, circuit formation, brain evolution and human pathology. Because of their short lifespan, CRs have been pictured as a purely developmental cell type, whose production and active elimination are both required for correct brain development. In this review, we present some of the findings that allow us to better appreciate the identity and diversity of this very special cell type, and propose a unified definition of what should be considered a Cajal-Retzius cell, especially when working with non-mammalian species or organoids. In addition, we highlight a flurry of recent studies pointing to the importance of CRs in the assembly of functional and dysfunctional cortical networks.
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Temporal control of neuronal wiring.
Wiring an animal brain is a complex process involving a staggering number of cell-types born at different times and locations in the developing brain. Incorporation of these cells into precise circuits with high fidelity is critical for animal survival and behavior. Assembly of neuronal circuits is heavily dependent upon proper timing of wiring programs, requiring neurons to express specific sets of genes (sometimes transiently) at the right time in development. While cell-type specificity of genetic programs regulating wiring has been studied in detail, mechanisms regulating proper timing and coordination of these programs across cell-types are only just beginning to emerge. In this review, we discuss some temporal regulators of wiring programs and how their activity is controlled over time and space. A common feature emerges from these temporal regulators - they are induced by cell-extrinsic cues and control transcription factors capable of regulating a highly cell-type specific set of target genes. Target specificity in these contexts comes from cell-type specific transcription factors. We propose that the spatiotemporal specificity of wiring programs is controlled by the combinatorial activity of temporal programs and cell-type specific transcription factors. Going forward, a better understanding of temporal regulators will be key to understanding the mechanisms underlying brain wiring, and will be critical for the development of in vitro models like brain organoids.