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Precision Medicine in Parkinson's Disease Using Induced Pluripotent Stem Cells.
Parkinson's disease (PD) is one of the most devastating neurological diseases; however, there is no effective cure yet. The availability of human induced pluripotent stem cells (iPSCs) provides unprecedented opportunities to understand the pathogenic mechanism and identification of new therapy for PD. Here a new model system of PD, including 2D human iPSC-derived midbrain dopaminergic (mDA) neurons, 3D iPSC-derived midbrain organoids (MOs) with cellular complexity, and more advanced microphysiological systems (MPS) with 3D organoids, is introduced. It is believed that successful integrations and applications of iPSC, organoid, and MPS technologies can bring new insight on PD's pathogenesis that will lead to more effective treatments for this debilitating disease.
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Modeling Lewy body disease with SNCA triplication iPSC-derived cortical organoids and identifying therapeutic drugs.
Aggregated α-synuclein (α-SYN) proteins, encoded by the SNCA gene, are hallmarks of Lewy body disease (LBD), affecting multiple brain regions. However, the specific mechanisms underlying α-SYN pathology in cortical neurons, crucial for LBD-associated dementia, remain unclear. Here, we recapitulated α-SYN pathologies in human induced pluripotent stem cells (iPSCs)-derived cortical organoids generated from patients with LBD with SNCA gene triplication. Single-cell RNA sequencing, combined with functional and molecular validation, identified synaptic and mitochondrial dysfunction in excitatory neurons exhibiting high expression of the SNCA gene, aligning with observations in the cortex of autopsy-confirmed LBD human brains. Furthermore, we screened 1280 Food and Drug Administration-approved drugs and identified four candidates (entacapone, tolcapone, phenazopyridine hydrochloride, and zalcitabine) that inhibited α-SYN seeding activity in real-time quaking-induced conversion assays with human brains, reduced α-SYN aggregation, and alleviated mitochondrial dysfunction in SNCA triplication organoids and excitatory neurons. Our findings establish human cortical LBD models and suggest potential therapeutic drugs targeting α-SYN aggregation for LBD.
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Excitatory cortical neurons from CDKL5 deficiency disorder patient-derived organoids show early hyperexcitability not identified in neurogenin2 induced neurons.
CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy resulting from variants in cyclin-dependent kinase-like 5 (CDKL5) that lead to impaired kinase activity or loss of function. CDD is one of the most common genetic etiologies identified in epilepsy cohorts. To study how CDKL5 variants impact human neuronal activity, gene expression and morphology, CDD patient-derived induced pluripotent stem cells and their isogenic controls were differentiated into excitatory neurons using either an NGN2 induction protocol or a guided cortical organoid differentiation. Patient-derived neurons from both differentiation paradigms had decreased phosphorylated EB2, a known molecular target of CDKL5. Induced neurons showed no detectable differences between cases and isogenic controls in network activity using a multielectrode array, or in MAP2+ neurite length, and only two genes were differentially expressed. However, patient-derived neurons from the organoid differentiation showed increased synchrony and weighted mean firing rate on the multielectrode array within the first month of network maturation. CDD patient-derived cortical neurons had lower expression of CDKL5 and HS3ST1, which may change the extracellular matrix around the synapse and contribute to hyperexcitability. Similar to the induced neurons, there were no differences in neurite length across or within patient-control cell lines. Induced neurons have poor cortical specification while the organoid derived neurons expressed cortical markers, suggesting that the changes in neuronal excitability and gene expression are specific to cortical excitatory neurons. Examining molecular mechanisms of early hyperexcitability in cortical neurons is a promising avenue for identification of CDD therapeutics.
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Development of Organoids from Mouse Pituitary as In Vitro Model to Explore Pituitary Stem Cell Biology.
The pituitary is the master endocrine gland regulating key physiological processes, including body growth, metabolism, sexual maturation, reproduction, and stress response. More than a decade ago, stem cells were identified in the pituitary gland. However, despite the application of transgenic in vivo approaches, their phenotype, biology, and role remain unclear. To tackle this enigma, a new and innovative organoid in vitro model is developed to deeply unravel pituitary stem cell biology. Organoids represent 3D cell structures that, under defined culture conditions, self-develop from a tissue's (epithelial) stem cells and recapitulate multiple hallmarks of those stem cells and their tissue. It is shown here that mouse pituitary-derived organoids develop from the gland's stem cells and faithfully recapitulate their in vivo phenotypic and functional characteristics. Among others, they reproduce the activation state of the stem cells as in vivo occurring in response to transgenically inflicted local damage. The organoids are long-term expandable while robustly retaining their stemness phenotype. The new research model is highly valuable to decipher the stem cells' phenotype and behavior during key conditions of pituitary remodeling, ranging from neonatal maturation to aging-associated fading, and from healthy to diseased glands. Here, a detailed protocol is presented to establish mouse pituitary-derived organoids, which provide a powerful tool to dive into the yet enigmatic world of pituitary stem cells.
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GLP-1R agonist semaglutide protects human forebrain organoids from cholesterol-induced neurotoxicity.
INTRODUCTION: Dysregulated cholesterol metabolism represents a critical metabolic stressor in the central nervous system, contributing to neuronal injury across multiple neurological conditions, including Alzheimer's disease (AD). While glucagon-like peptide-1 receptor (GLP-1R) agonists show neuroprotective potential, their capacity to directly mitigate cholesterol-induced metabolic stress in human neural cells remains to be established. METHODS: Here, we modeled metabolic stress using human induced pluripotent stem cell-derived forebrain organoids exposed to cholesterol overload. The protective effects of the GLP-1R agonist semaglutide were characterized by integrating bulk/single-cell transcriptomics, calcium imaging, and biochemical assays. Furthermore, clinical translatability was supported by mapping organoid expression signatures against human post mortem neurodegenerative brain datasets. RESULTS: Cholesterol overload induced cellular stress and transcriptomic alterations that partially overlapped with AD-associated signatures. Semaglutide protected neural cells from lipotoxic injury. Intracellularly, GLP-1R activation engaged the cyclic adenosine 3',5'-monophosphate-protein kinase A and phosphoinositide 3 kinase-protein kinase B-mechanistic target of rapamycin signaling pathways, consistent with reduced lipid droplet accumulation and oxidative stress. Intercellularly, single-cell analysis indicated partial preservation of disrupted cellular communication, including the neurotrophic midkine signaling network. Functionally, semaglutide stabilized cellular calcium activity patterns under metabolic stress. DISCUSSION: These findings highlight the role of cholesterol homeostasis in maintaining neuronal integrity and position GLP-1R signaling as a candidate protective axis under metabolic stress, offering insights into therapeutic strategies for AD and broader neurodegenerative disorders.
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Examining the NEUROG2 lineage and associated gene expression in human cortical organoids.
Proneural genes are conserved drivers of neurogenesis across the animal kingdom. How their functions have adapted to guide human-specific neurodevelopmental features is poorly understood. Here, we mined transcriptomic data from human fetal cortices and generated from human embryonic stem cell-derived cortical organoids (COs) to show that NEUROG1 and NEUROG2 are most highly expressed in basal neural progenitor cells, with pseudotime trajectory analyses indicating that NEUROG1-derived lineages predominate early and NEUROG2 lineages later. Using ChIP-qPCR, gene silencing and overexpression studies in COs, we show that NEUROG2 is necessary and sufficient to directly transactivate known target genes (NEUROD1, EOMES, RND2). To identify new targets, we engineered NEUROG2-mCherry knock-in human embryonic stem cells for CO generation. The mCherry-high CO cell transcriptome is enriched in extracellular matrix-associated genes, and two genes associated with human-accelerated regions: PPP1R17 and FZD8. We show that NEUROG2 binds COL1A1, COL3A1 and PPP1R17 regulatory elements, and induces their ectopic expression in COs, although NEUROG2 is not required for this expression. Neurog2 similarly induces Col3a1 and Ppp1r17 in murine P19 cells. These data are consistent with a conservation of NEUROG2 function across mammalian species.
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Vacuolar change in Alzheimer's disease.
A retrospective neuropathologic study of brains from 66 patients with Alzheimer's disease (AD) demonstrated the presence of a vacuolar change (VC) in 50 cases that was virtually indistinguishable histologically from the spongiform change characteristic of Creutzfeldt-Jakob disease (CJD). Indeed, in several instances, there was initial diagnostic confusion with CJD. Unlike the spongiform change in CJD, however, VC was almost entirely restricted to the medial temporal cortex and amygdala. Furthermore, the severity of VC was usually less intense than the spongiform change observed in cases of CJD with severe neurologic impairment. The VC could be readily distinguished from the fine microvacuolation of the upper layers of the isocortex reported in a number of different conditions, including AD. It also differed from the status spongiosus of the cerebral cortex that occurs in advanced AD and CJD as well as in other degenerative diseases. The artifactual rarefaction that occurs in improperly processed paraffin-embedded brain tissue was excluded as a contributory factor to the VC. Since VC does not invariably occur in AD, it conceivably could represent a subtype of this disorder or may represent a variant of the pathologic changes that can occur. Its relationship to CJD or other slow virus disorders is to date unknown but unlikely.
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Human forebrain organoids reveal connections between valproic acid exposure and autism risk.
Valproic acid (VPA) exposure as an environmental factor that confers risk of autism spectrum disorder (ASD), its functional mechanisms in the human brain remain unclear since relevant studies are currently restricted to two-dimensional cell cultures and animal models. To identify mechanisms by which VPA contribute to ASD risk in human, here we used human forebrain organoids (hFOs), in vitro derived three-dimensional cell cultures that recapitulate key human brain developmental features. We identified that VPA exposure in hFOs affected the expression of genes enriched in neural development, synaptic transmission, oxytocin signaling, calcium, and potassium signaling pathways, which have been implicated in ASD. Genes (e.g., CAMK4, CLCN4, DPP10, GABRB3, KCNB1, PRKCB, SCN1A, and SLC24A2) that affected by VPA were significantly overlapped with those dysregulated in brains or organoids derived from ASD patients, and known ASD risk genes, as well as genes in ASD risk-associated gene coexpression modules. Single-cell RNA sequencing analysis showed that VPA exposure affected the expression of genes in choroid plexus, excitatory neuron, immature neuron, and medial ganglionic eminence cells annotated in hFOs. Microelectrode array further identified that VPA exposure in hFOs disrupted synaptic transmission. Taken together, this study connects VPA exposure to ASD pathogenesis using hFOs, which is valuable for illuminating the etiology of ASD and screening for potential therapeutic targets.
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Hypothalamic-pituitary organoid generation through the recapitulation of organogenesis.
This paper overviews the development and differentiation of the hypothalamus and pituitary gland from embryonic stem (ES) and induced pluripotent stem (iPS) cells. It is important to replicate the developmental process in vivo to create specific cells/organoids from ES/iPS cells. We also introduce the latest findings and discuss future issues for clinical application. Neuroectodermal progenitors are induced from pluripotent stem cells by strictly removing exogenous patterning factors during the early differentiation period. The induced progenitors differentiate into rostral hypothalamic neurons, in particular magnocellular vasopressin+ neurons. In three-dimensional cultures, ES/iPS cells differentiate into hypothalamic neuroectoderm and nonneural head ectoderm adjacently. Rathke's pouch-like structures self-organize at the interface between the two layers and generate various endocrine cells, including corticotrophs and somatotrophs. Our next objective is to sophisticate our stepwise methodology to establish a novel transplantation treatment for hypopituitarism and apply it to developmental disease models.
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Generation, differentiation, and potential of three radial glial subtypes in human cortical organoids.
Radial glia are the principal neural stem cells in the developing human cerebral cortex and have been classified as three molecularly distinct subtypes: ventricular radial glia (vRG), outer radial glia (oRG), and truncated radial glia (tRG). Human cortical organoids (hCOs) from human pluripotent stem cells that recapitulate the developmental program of the human cortex have shown this progenitor diversity. vRG and oRG are readily generated and identified in hCOs from most differentiation protocols with oRG emergence dependent on specific signaling pathways, such as LIF/STAT3 supplementation. However, tRGs that have only recently been defined at the molecular level have not been systematically examined in any organoid system. Here we review the biology, signaling, and lineage potential of each radial glial subtype and assess how faithfully they are represented in cortical organoids. We highlight and discuss the studies on the tRG from hCOs. We discuss data consistent with latent tRG competence in hCOs, including ependymal cell generation from radial glia within organoids, CRYAB-positive progenitors in three-dimensional culture systems, and tRG-associated transcriptomic shifts upon genetic perturbation, while noting that definitive tRG identification has not yet been achieved. However, definitive identification through combinatorial marker co-expression and morphological validation has not yet been achieved. Faithfully establishing molecular signatures and signaling frameworks for tRG and their existence in hCOs will provide the foundation for systemically investigating and function of this cell type in vitro, and we discuss future directions for resolving whether tRG are generated during the neurogenesis-to-gliogenesis transition. [BMB Reports 2026; 59(8): 373-383].