Inflammatory responses revealed through HIV infection of microglia-containing cerebral organoids

Journal of Neuroinflammation, Год журнала: 2025, Номер 22(1)

Опубликована: Фев. 10, 2025

Cerebral organoids (COs) are valuable tools for studying the intricate interplay between glial cells and neurons in brain development disease, including HIV-associated neuroinflammation. We developed a novel approach to generate microglia containing COs (CO-iMs) by co-culturing hematopoietic progenitors inducing pluripotent stem cells. This allowed differentiation of within concomitantly with neuronal progenitors. Compared conventional COs, CO-iMs were more efficient at generating CD45+/CD11b+/Iba-1+ presented physiologically relevant proportion (~ 7%). substantially increased expression microglial homeostatic sensome markers as well complement cascade. susceptible HIV infection, resulting significant increase several pro-inflammatory cytokines/chemokines, which abrogated addition antiretrovirals. Thus, CO-iM is robust model deciphering neuropathogenesis, neuroinflammation, viral infections 3D culture system.

Язык: Английский

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“Focused Ultrasound-mediated Drug Delivery in Humans – a Path Towards Translation in Neurodegenerative Diseases”

Pharmaceutical Research, Год журнала: 2022, Номер 39(3), С. 427 - 439

Опубликована: Март 1, 2022

Abstract The blood-brain barrier (BBB) has a major protective function in preventing the entry of harmful molecules into brain, but is simultaneously limiting delivery drugs, restricting their potential clinical application neurodegenerative diseases. Recent preclinical evidence demonstrates that following focused ultrasound with microbubbles (FUS+MB), BBB becomes reversibly accessible to compounds normally are brain-impermeable, suggesting FUS+MB as promising new platform for therapeutic agents central nervous system. As step towards translation, small cohort studies were performed demonstrating safe opening Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS) patients FUS+MB, however improved drug not yet been achieved human. Simultaneously, rapid progress human induced pluripotent stem cell (hiPSC) modeling technology allowed development novel patient-derived vitro model reacts can be used answer fundamental questions responses health disease. This review summarizes key features contribute limited delivery, recapitulates recent advances mediated vivo context disorders, highlights strategies fast-track translation improve bioavailability drugs brain. With effective application, this innovative may open avenues interventions diseases leading outcomes patients.

Язык: Английский

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Unlocking Neural Function with 3D In Vitro Models: A Technical Review of Self-Assembled, Guided, and Bioprinted Brain Organoids and Their Applications in the Study of Neurodevelopmental and Neurodegenerative Disorders

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(13), С. 10762 - 10762

Опубликована: Июнь 28, 2023

Understanding the complexities of human brain and its associated disorders poses a significant challenge in neuroscience. Traditional research methods have limitations replicating intricacies, necessitating development vitro models that can simulate structure function. Three-dimensional models, including organoids, cerebral bioprinted functionalized offer promising platforms for studying development, physiology, disease. These accurately replicate key aspects anatomy, gene expression, cellular behavior, enabling drug discovery toxicology studies while providing insights into human-specific phenomena not easily studied animal models. The use human-induced pluripotent stem cells has revolutionized generation 3D structures, with various techniques developed to generate specific regions. advancements facilitate study function, overcoming previous due scarcity samples. This technical review provides an overview current cortex, their characterization, limitations, explores state art future directions field, focus on applications neurodevelopmental neurodegenerative disorders.

Язык: Английский

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The Impact of the Cellular Environment and Aging on Modeling Alzheimer's Disease in 3D Cell Culture Models

Advanced Science, Год журнала: 2023, Номер 10(8)

Опубликована: Янв. 15, 2023

Creating a cellular model of Alzheimer's disease (AD) that accurately recapitulates pathology has been longstanding challenge. Recent studies showed human AD neural cells, integrated into three-dimensional (3D) hydrogel matrix, display key features neuropathology. Like in the brain, extracellular matrix (ECM) plays critical role determining rate neuropathogenesis hydrogel-based 3D models. Aging, greatest risk factor for AD, significantly alters brain ECM properties. Therefore, it is important to understand how age-associated changes affect accumulation pathogenic molecules, neuroinflammation, and neurodegeneration patients vitro In this review, mechanistic hypotheses presented address impact properties their with aging on AD-related dementias. Altered characteristics aged brains, including stiffness, pore size, composition, will contribute pathogenesis by modulating accumulation, propagation, spreading molecules AD. Emerging models differing provide an exciting opportunity study pathogenesis, providing novel insights. Understanding should also improve modeling systems.

Язык: Английский

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Organelle mapping in dendrites of human iPSC-derived neurons reveals dynamic functional dendritic Golgi structures

Cell Reports, Год журнала: 2023, Номер 42(7), С. 112709 - 112709

Опубликована: Июнь 30, 2023

Secretory pathways within dendrites of neurons have been proposed for local transport newly synthesized proteins. However, little is known about the dynamics secretory system and whether organelles are transient or stable structures. Here, we quantify spatial dynamic behavior dendritic Golgi endosomes during differentiation human generated from induced pluripotent stem cells (iPSCs). In early neuronal development, before migration, entire apparatus transiently translocates soma into dendrites. mature neurons, elements, containing cis trans cisternae, transported along dendrites, in an actin-dependent process. Dendritic outposts display bidirectional movement. Similar structures were observed cerebral organoids. Using retention using selective hooks (RUSH) system, resident proteins efficiently endoplasmic reticulum. This study reveals dynamic, functional a map investigating dendrite trafficking neurons.

Язык: Английский

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Cerebral organoids derived from patients with Alzheimer’s disease with PSEN1/2 mutations have defective tissue patterning and altered development

Cell Reports, Год журнала: 2023, Номер 42(11), С. 113310 - 113310

Опубликована: Окт. 20, 2023

During the past two decades, induced pluripotent stem cells (iPSCs) have been widely used to study human neural development and disease. Especially in field of Alzheimer's disease (AD), remarkable effort has put into investigating molecular mechanisms behind this Then, with advent 3D neuronal cultures cerebral organoids (COs), several studies demonstrated that model can adequately mimic familial sporadic AD. Therefore, we created an AD-CO using iPSCs derived from patients AD forms explored early events progression pathogenesis. Our COs three AD-iPSC lines PSEN1(A246E) or PSEN2(N141I) mutations developed AD-specific markers vitro, yet they also uncover tissue patterning defects altered development. These findings are complemented by single-cell sequencing data confirming observation uncovering neurons AD-COs likely differentiate prematurely.

Язык: Английский

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SIMS: A deep-learning label transfer tool for single-cell RNA sequencing analysis

Cell Genomics, Год журнала: 2024, Номер 4(6), С. 100581 - 100581

Опубликована: Май 31, 2024

Cell atlases serve as vital references for automating cell labeling in new samples, yet existing classification algorithms struggle with accuracy. Here we introduce SIMS (scalable, interpretable machine learning single cell), a low-code data-efficient pipeline single-cell RNA classification. We benchmark against datasets from different tissues and species. demonstrate SIMS's efficacy classifying cells the brain, achieving high accuracy even small training sets (<3,500 cells) across samples. accurately predicts neuronal subtypes developing shedding light on genetic changes during differentiation postmitotic fate refinement. Finally, apply to of cortical organoids predict identities uncover variations between lines. identifies cell-line differences misannotated lineages human derived pluripotent stem Altogether, show that is versatile robust tool cell-type datasets.

Язык: Английский

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Brain organoid: a 3D technology for investigating cellular composition and interactions in human neurological development and disease models in vitro

Stem Cell Research & Therapy, Год журнала: 2021, Номер 12(1)

Опубликована: Июль 31, 2021

Abstract The study of human brain physiology, including cellular interactions in normal and disease conditions, has been a challenge due to its complexity unavailability. Induced pluripotent stem cell (iPSC) is indispensable the pathophysiology neurological disorders. Nevertheless, monolayer systems lack cytoarchitecture necessary for modeling. Brain organoids generated from cells supply an ideal environment model both brain. This review article discusses composition among neural lineage non-central nervous system types organoids, current studies, future perspectives organoid research. Ultimately, promise unveil previously inaccessible features neurobiology that emerge complex improve our mechanistic understanding development diseases. Graphical abstract

Язык: Английский

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A sporadic Alzheimer's blood-brain barrier model for developing ultrasound-mediated delivery of Aducanumab and anti-Tau antibodies

Theranostics, Год журнала: 2022, Номер 12(16), С. 6826 - 6847

Опубликована: Янв. 1, 2022

Rationale:The blood-brain barrier (BBB) is a major impediment to therapeutic intracranial drug delivery for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD).Focused ultrasound applied together with microbubbles (FUS +MB ) novel technique transiently open BBB and increase delivery.Evidence suggests that FUS safe, however, effects on human cells, especially in context AD, remain sparsely investigated.In addition, there currently are no cell platforms test -mediated delivery.Methods: Here we generated cells (induced brain endothelial-like (iBECs) astrocytes (iAstrocytes)) from apolipoprotein E gene allele E4 (APOE4, high sporadic AD risk) E3 (APOE3, lower carrying patient-derived induced pluripotent stem (iPSCs).We established mono-and co-culture models control investigate phenotype screen two potentially antibodies, an Aducanumab-analogue (Aduhelm TM ; anti-amyloid-β) anti-Tau antibody, RNF5.We then developed hydrogel-based 2.5D model as step towards more physiologically relevant platform.Results: When compared untreated RNF5 was significantly increased (up 1.73 fold), across Transwell-based following treatment.Our results also demonstrated safety indicated by minimal changes iBEC transcriptome well little or iAstrocyte viability inflammatory responses within first 24 h post .Furthermore, successful formation our (1.4 fold) .Conclusion: Our demonstrate robust reproducible approach utilize patient screening vitro.With such platform research previously not reported, it has potential identify -deliverable drugs cell-and patient-specific , accelerating use modality AD.

Язык: Английский

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Patient-Derived In Vitro Models of Microglial Function and Synaptic Engulfment in Schizophrenia

Biological Psychiatry, Год журнала: 2022, Номер 92(6), С. 470 - 479

Опубликована: Янв. 19, 2022

Язык: Английский

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