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Neural Organoids and the Precautionary Principle.
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The link between amyloid β and ferroptosis pathway in Alzheimer's disease progression.
Alzheimer's disease (AD) affects millions of people worldwide and represents the most prevalent form of dementia. Treatment strategies aiming to interfere with the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs), the two major AD hallmarks, have shown modest or no effect. Recent evidence suggests that ferroptosis, a type of programmed cell death caused by iron accumulation and lipid peroxidation, contributes to AD pathogenesis. The existing link between ferroptosis and AD has been largely based on cell culture and animal studies, while evidence from human brain tissue is limited. Here we evaluate if Aβ is associated with ferroptosis pathways in post-mortem human brain tissue and whether ferroptosis inhibition could attenuate Aβ-related effects in human brain organoids. Performing positive pixel density scoring on immunohistochemically stained post-mortem Brodmann Area 17 sections revealed that the progression of AD pathology was accompanied by decreased expression of nuclear receptor co-activator 4 and glutathione peroxidase 4 in the grey matter. Differentiating between white and grey matter, allowed for a more precise understanding of the disease's impact on different brain regions. In addition, ferroptosis inhibition prevented Aβ pathology, decreased lipid peroxidation and restored iron storage in human AD iPSCs-derived brain cortical organoids at day 50 of differentiation. Differential gene expression analysis of RNAseq of AD organoids compared to isogenic controls indicated activation of the ferroptotic pathway. This was also supported by results from untargeted proteomic analysis revealing significant changes between AD and isogenic brain organoids. Determining the causality between the development of Aβ plaques and the deregulation of molecular pathways involved in ferroptosis is crucial for developing potential therapeutic interventions.
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Platelets as models: use and limitations.
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Research Comparing iPSC-Derived Neural Organoids to Ex Vivo Brain Tissue of Postmortem Donors: Identity After Life?
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Cerebral Cortex Generated from Pluripotent Stem Cells to Model Corticogenesis and Rebuild Cortical Circuits: In Vitro Veritas?
Organoids and cells generated in vitro from pluripotent stem cells (PSCs) are considered to be robust models of development and a conceivable source of transplants for putative cell therapy. However, a fundamental question about organoids and cells generated from PSCs is as follows: do they faithfully reproduce the in vivo tissue they are supposed to mimic and replace? This question is particularly relevant to complex tissues such as the cerebral cortex. In this review, we have tackled this issue by comparing cerebral cortices generated in vitro from PSCs to the in vivo cortex, with a particular focus on their respective cellular composition, molecular and epigenetic signatures, and brain connectivity. In short, in vitro cortex generated from PSCs reproduces most of the cardinal features of the in vivo cortex, including temporal corticogenesis and connectivity when PSC-derived cortical cells are grafted in recipient mouse cortex. However, compared to in vivo cortex, in vitro cortex lacks microglia and blood vessels and is less mature. Recent experiments show that the brain of the transplanted host provides these missing cell types together with an environment that promotes the synaptic maturation of the cortical transplant. Taken together, these data suggest that corticogenesis is largely intrinsic and well recapitulated in vitro, while the full maturation of cortical cells requires additional environmental clues. Finally, we propose some lines of work to improve corticogenesis from PSCs as a tool to model corticogenesis and rebuild cortical circuits.
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Recent Overview of the Use of iPSCs Huntington's Disease Modeling and Therapy.
Huntington's disease (HD) is an inherited, autosomal dominant, degenerative disease characterized by involuntary movements, cognitive decline, and behavioral impairment ending in death. HD is caused by an expansion in the number of CAG repeats in the huntingtin gene on chromosome 4. To date, no effective therapy for preventing the onset or progression of the disease has been found, and many symptoms do not respond to pharmacologic treatment. However, recent results of pre-clinical trials suggest a beneficial effect of stem-cell-based therapy. Induced pluripotent stem cells (iPSCs) represent an unlimited cell source and are the most suitable among the various types of autologous stem cells due to their patient specificity and ability to differentiate into a variety of cell types both in vitro and in vivo. Furthermore, the cultivation of iPSC-derived neural cells offers the possibility of studying the etiopathology of neurodegenerative diseases, such as HD. Moreover, differentiated neural cells can organize into three-dimensional (3D) organoids, mimicking the complex architecture of the brain. In this article, we present a comprehensive review of recent HD models, the methods for differentiating HD-iPSCs into the desired neural cell types, and the progress in gene editing techniques leading toward stem-cell-based therapy.
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Characterization of cerebroside sulfotransferase from rat brain.
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Structure of the somatic appendages of neurons of locus coeruleus in cat.
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Integrated RNA Sequencing Reveals Epigenetic Impacts of Diesel Particulate Matter Exposure in Human Cerebral Organoids.
Autism spectrum disorder (ASD) manifests early in childhood. While genetic variants increase risk for ASD, a growing body of literature has established that in utero chemical exposures also contribute to ASD risk. These chemicals include air-based pollutants like diesel particulate matter (DPM). A combination of single-cell and direct transcriptomics of DPM-exposed human-induced pluripotent stem cell-derived cerebral organoids revealed toxicogenomic effects of DPM exposure during fetal brain development. Direct transcriptomics, sequencing RNA bases via Nanopore, revealed that cerebral organoids contain extensive RNA modifications, with DPM-altering cytosine methylation in oxidative mitochondrial transcripts expressed in outer radial glia cells. Single-cell transcriptomics further confirmed an oxidative phosphorylation change in cell groups such as outer radial glia upon DPM exposure. This approach highlights how DPM exposure perturbs normal mitochondrial function and cellular respiration during early brain development, which may contribute to developmental disorders like ASD by altering neurodevelopment.
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Rapid 3D phenotypic analysis of neurons and organoids using data-driven cell segmentation-free machine learning.
Phenotypic profiling of large three-dimensional microscopy data sets has not been widely adopted due to the challenges posed by cell segmentation and feature selection. The computational demands of automated processing further limit analysis of hard-to-segment images such as of neurons and organoids. Here we describe a comprehensive shallow-learning framework for automated quantitative phenotyping of three-dimensional (3D) image data using unsupervised data-driven voxel-based feature learning, which enables computationally facile classification, clustering and advanced data visualization. We demonstrate the analysis potential on complex 3D images by investigating the phenotypic alterations of: neurons in response to apoptosis-inducing treatments and morphogenesis for oncogene-expressing human mammary gland acinar organoids. Our novel implementation of image analysis algorithms called Phindr3D allowed rapid implementation of data-driven voxel-based feature learning into 3D high content analysis (HCA) operations and constitutes a major practical advance as the computed assignments represent the biology while preserving the heterogeneity of the underlying data. Phindr3D is provided as Matlab code and as a stand-alone program (https://github.com/DWALab/Phindr3D).