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iPSC-derived neural organoids in dementia research: Recent advances and future directions.
Neural organoids are self-assembled three-dimensionally shaped aggregates generated from pluripotent stem cells for the purpose of generating brain-like structures. The features of the disease, from molecular to functional levels, can be recapitulated by neural organoids derived from patient induced pluripotent stem cells (iPSCs). These features are not fully reproduced by other culture systems or in vivo models. Neural organoids have been applied to model dementia including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis/frontotemporal dementia, and they have recapitulated aspects of their complex pathophysiology, including neuronal network dysfunction and accumulation of pathogenic proteins. Although research using neural organoids still faces challenges such as heterogeneity and the absence of non-neural lineage cells, these limitations are being progressively addressed. Recent advances, including the integration of gene-editing technologies and the co-assembly of organoids with specific cell types, have demonstrated the remarkable potential of this approach. This article reviews current research on iPSC-derived neural organoids for dementia, discussing both the technical hurdles and the potential for translational applications.
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Peroxisomes (microbodies) in human glial tumors. a cytochemical ultrastructural study.
Morphologically and cytochemically defined peroxisomes (microbodies) were demonstrated in a series of 11 human glial tumors. The cytochemical methods used were diaminobenzidine method for catalase and a tetrazolium salt-phenozine methosulfate method for D-amino-acid oxidase. Ultrastructurally, the peroxisomes were found as single membrane limited organelles with a granular matrix. Marginal plates as well as continuities with the smooth endoplasmic reticulum could be demonstrated. Peroxisomes were found most abundantly in subependymal giant cell astrocytomas, to a lesser number in astrocytomas and least abundantly in glioblastomas.
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Stem cells, organoids and their applications for human diseases: Special issue of BMB Reports in 2023.
Studying human biology has been challenging with conventional animal models or two-dimensional (2D) cultured cell lines. Recent advances in stem cell biology have made it possible to culture stem cells in vitro, leading to the establishment of in vitro three-dimensional (3D) organ-like structures known as organoids. Organoids are self-organizing 3D miniature tissues that mimic the tissue architecture and functionality of in vivo counterparts. Currently, organoids can be established for multiple tissues such as the intestine, brain, kidney, prostate, pancreas, liver, bladder, heart, and retina, either from pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), or adult stem cells (AdSCs). In addition to normal organoids, patient-derived tumor organoids have been established from various human tumors such as pancreatic, colorectal, breast, liver, prostate, and bladder tumors. Also, bioengineering technologies including biomaterial and scaffold fabrication, bioprinting, and microfluidics have been recently applied to create more mature and complex organoids and miniature tissues in vitro. Incorporating recently advanced computational analyses including multi-omics profiling and bioinformatics further facilitated the process of using human organoids as a novel platform for human disease modeling, drug screening to identify potential targets and novel therapeutics, and the development of precision medicine and regenerative therapies. [BMB Reports 2023; 56(1): 1].
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Using multi-organ culture systems to study Parkinson's disease.
In recent years, it has been revealed that Parkinson's disease pathology may begin to manifest in the gastrointestinal track at a much earlier time point than in the brain. This paradigm shift has been suggested following evidence in humans that has been reproduced in animal models. Since rodent models cannot recapitulate many of the human disease features, human induced pluripotent stem cells derived from Parkinson's patients have been used to generate brain organoids, greatly contributing to our understanding of the disease pathophysiology. To understand the multifaced aspects of Parkinson's disease, it may be desirable to expand the complexity of these models, to include different brain regions, vasculature, immune cells as well as additional diverse organ-specific organoids such as gut and intestine. Furthermore, the contribution of gut microbiota to disease progression cannot be underestimated. Recent biotechnological advances propose that such combinations may be feasible. Here we discuss how this need can be met and propose that additional brain diseases can benefit from this approach.
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Direct visualization of the transition status during neural differentiation by dual-fluorescent reporter human pluripotent stem cells.
Human induced pluripotent stem cells (hiPSCs) can differentiate into neurons and glia via neural progenitor cells and are widely used for neurogenic studies. However, directly visualizing the transition status during the neural differentiation of live cells is difficult. Here, targeting NEUROG2 (NGN2) and TUBB3 as markers of neurogenic cells and neurons, respectively, we established TUBB3EGFP/NGN2TagRFP dual-reporter hiPSCs using CRISPR-Cas9 technology. We induced the differentiation of cortical neurons from dual-reporter hiPSCs, successfully visualizing cell-fate conversion in two-dimensional (2D) culture and 3D organoids. The reporter cells were used to monitor drug effects to enhance neural induction, responses to gene knockdown, transplantation to the embryonic mouse brain, and live imaging at single-cell resolution. Notably, the earliest REELIN-positive neurons showed a distinctive migration pattern, and their production was accelerated by HES1-function loss. Together, these results demonstrate the potential for dual-reporter hiPSCs in therapeutic neural regeneration strategies and studies on human cortical development.
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Vascular structures in brain tumors.
The blood vessels within brain tumors show alterations from the normal anatomy. Some of these seem to be related to an increased capacity to transfer materials between the lumen and the parenchyma and are probably intimately connected with the edema associated with the tumor. These alterations include fenestration, widened intercellular junctions, increase in pinocytotic vesicles, and infolding of the luminal surface. Other alterations are observed but their function is not as clear. The latter include an increase in the number of tubular bodies, the appearance of tubular structures within vacuoles, tubular arrays within the nuclear envelope and rough endoplasmic reticulum, and endothelial proliferation, among others.
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Differentiating visceral sensory ganglion organoids from induced pluripotent stem cells.
The ability to generate visceral sensory neurons (VSN) from induced pluripotent stem (iPS) cells may help to gain insights into how the gut-nerve-brain axis is involved in neurological disorders. We established a protocol to differentiate human iPS-cell-derived visceral sensory ganglion organoids (VSGOs). VSGOs exhibit canonical VSN markers, and single-cell RNA sequencing revealed heterogenous molecular signatures and developmental trajectories of VSGOs aligned with native VSN. We integrated VSGOs with human colon organoids on a microfluidic device and applied this axis-on-a-chip model to Alzheimer's disease. Our results suggest that VSN could be a potential mediator for propagating gut-derived amyloid and tau to the brain in an APOE4- and LRP1-dependent manner. Furthermore, our approach was extended to include patient-derived iPS cells, which demonstrated a strong correlation with clinical data.
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Distribution of lipids in subcellular particles of guinea-pig brain.
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Human brain organoids containing microglia that have arisen innately adapt to a β-amyloid challenge better than those in which microglia are integrated by co-culture.
BACKGROUND: Alzheimer disease (AD) is a heterogenous and multifactorial disease, and its pathology is partly driven by microglia and their activated phenotype. Brain organoids (BOs) are gaining prominence as a relevant model of the human brain for the study of AD; however, BOs are commonly devoid of microglia. To overcome this limitation, current protocols incorporate microglia through either (1) co-culture (BO co-culture), or (2) molecular manipulation at critical windows of BO development to have microglia arise innately (BO innate cultures). It is currently unclear whether the microglia incorporated into BOs by either of these two protocols differ in function. METHODS: At in vitro day 90, BO innate cultures and BO-co-cultures were challenged with the AD-related β-amyloid peptide (Aβ) for up to 72 h. After Aβ challenge, BOs were collected for immunoblotting. Immunoblots compared immunodensity and protein banding of Aβ and ionized calcium-binding adapter molecule 1 (IBA1, a marker of microglial activation) in BOs. The translational potential of these observations was supported using 56 human cortical samples from neurocognitively normal donors and patients with early-onset AD and late-onset AD. Statistical analyses were conducted using the Kruskal-Wallis test, a two-way ANOVA, or a simple linear regression, and where applicable, followed by Dunn's or Sidak's test. RESULTS: We show that BO co-cultures promote Aβ oligomerization as early as 24 h and this coincides with a significant increase in IBA1 levels. In contrast, the Aβs do not oligomerize in BO innate cultures and the IBA1 response was modest and only emerged after 48 h. In human cortical samples, we found IBA1 levels correlated with age at onset, age at death, and the putative diagnostic Aβ(1-42)/Aβ(1-40) ratio (particularly in their oligomeric forms) in a sex-dependent manner. CONCLUSIONS: Our unique observations suggest that BOs with innate microglia model the response of a healthy brain to Aβ, and by extension the initial stages of Aβ challenge. It would be impossible to model these early stages of pathogenesis in BOs where microglia are already compromised, such as those with microglia incorporated by co-culture.
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Studies on the submicrosomal fractions of bovine oligodendroglia: lipid composition and glycolipid biosynthesis.
Oligodendroglia were isolated from bovine brain, and a "crude" microsomal fraction obtained from cell homogenates was subfractionated into myelin (MP), plasma membranes (PM), Golgi (GF), smooth (SER) and rough (RER) endoplasmic membranes using discontinuous-sucrose gradient centrifugation. The submicrosomal fractions were characterized by ultrastructural examination and analysis of the specific organelle markers. The myelin and plasma membrane rich fractions contained characteristically the highest amounts of the lipid with lower mole percentages of total phospholipids and phosphatidylcholine, and higher concentrations of phosphatidylethanolamine (+ plasmalogens), cholesterol and galactolipids. Considerable amounts of the typical myelin galactolipids (galacto-cerebrosides, sulfatides and monogalactosyl diglycerides) were also found in the Golgi fraction (GF). The GF fraction had the greatest enrichment of glycolipid-forming galactosyltransferases, and the distribution of these enzymes correlated well with that of the Golgi marker enzymes. The results give evidence that intracellular Golgi apparatus of oligodendroglia is rich in the myelin-specific lipids, and suggest its involvement in the synthesis and processing of myelin lipids.