Expression of the transcription factor PU.1 induces the generation of microglia-like cells in human cortical organoids

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Jan. 20, 2022

Microglia play a role in the emergence and preservation of healthy brain microenvironment. Dysfunction microglia has been associated with neurodevelopmental neurodegenerative disorders. Investigating function human health disease challenging due to limited models available. Here, we develop method generate functional cortical organoids (hCOs) from embryonic stem cells (hESCs). We apply this system study during inflammation induced by amyloid-β (Aβ). The overexpression myeloid-specific transcription factor PU.1 generates microglia-like hCOs, producing mhCOs (microglia-containing hCOs), that engraft mouse brain. Single-cell transcriptomics reveals acquire cell cluster an intact complement chemokine system. Functionally, protect parenchyma cellular molecular damage caused Aβ. Furthermore, mhCOs, observed reduced expression Aβ-induced genes apoptosis, ferroptosis, Alzheimer's (AD) stage III. Finally, assess AD-associated highly expressed response Aβ using pooled CRISPRi coupled single-cell RNA sequencing mhCOs. In summary, provide protocol can be used fundamental translational studies as model investigate

Language: Английский

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iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer

Nature, Journal Year: 2023, Volume and Issue: 623(7986), P. 397 - 405

Published: Nov. 1, 2023

Language: Английский

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Microglial amyloid beta clearance is driven by PIEZO1 channels

Journal of Neuroinflammation, Journal Year: 2022, Volume and Issue: 19(1)

Published: June 15, 2022

Microglia are the endogenous immune cells of brain and act as sensors pathology to maintain homeostasis eliminate potential threats. In Alzheimer's disease (AD), toxic amyloid beta (Aβ) accumulates in forms stiff plaques. late-onset AD accounting for 95% all cases, this is thought be due reduced clearance Aβ. Human genome-wide association studies animal models suggest that results from aberrant function microglia. While impact neurochemical pathways on microglia had been broadly studied, mechanical receptors regulating microglial functions remain largely unexplored.Here we showed a mechanotransduction ion channel, PIEZO1, expressed functional human mouse We used small molecule agonist, Yoda1, study how activation PIEZO1 affects AD-related induced pluripotent stem cell (iPSC)-derived microglia-like (iMGL) under controlled laboratory experiments. Cell survival, metabolism, phagocytosis lysosomal activity were assessed using real-time assays. To evaluate effect vivo, 5-month-old 5xFAD male mice infused daily with Yoda1 two weeks through intracranial cannulas. Microglial Iba1 expression Aβ quantified immunohistochemistry confocal microscopy. Published datasets in-depth analysis gene related subpopulations.We show orchestrates by enhancing phagocytosis, activity. inhibited PIEZO1-mediated calcium transients, whereas selective improved resulting both AD. Moreover, was associated unique transcriptional phenotype indicated assessment cellular single-cell datasets.These indicate compromised could channels alleviated burden. Pharmacological regulation these mechanoreceptors represent novel therapeutic paradigm

Language: Английский

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Microglia-containing human brain organoids for the study of brain development and pathology

Molecular Psychiatry, Journal Year: 2022, Volume and Issue: 28(1), P. 96 - 107

Published: Dec. 6, 2022

Microglia are resident immune cells in the central nervous system, playing critical roles brain development and homeostasis. Increasing evidence has implicated microglia dysfunction pathogenesis of various disorders ranging from psychiatric to neurodegenerative diseases. Using a human cell-based model illuminate functional mechanisms will promote pathological studies drug development. The recently developed microglia-containing organoids (MC-HBOs), in-vitro three-dimensional cell cultures that recapitulate key features brain, have provided new avenue pathology. However, MC-HBOs generated different methods differ origin, proportion, fidelity within organoids, may produced inconsistent results. To help researchers develop robust reproducible recapitulates in-vivo signatures study pathology, this review summarized current used generate opinions on use for disease modeling studies.

Language: Английский

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The role of gamma oscillations in central nervous system diseases: Mechanism and treatment

Frontiers in Cellular Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: July 29, 2022

Gamma oscillation is the synchronization with a frequency of 30-90 Hz neural oscillations, which are rhythmic electric processes neuron groups in brain. The inhibitory interneuron network necessary for production gamma but certain disruptions such as brain inflammation, oxidative stress, and metabolic imbalances can cause this to malfunction. oscillations specifically control connectivity between different regions, crucial perception, movement, memory, emotion. Studies have linked abnormal conditions central nervous system, including Alzheimer's disease, Parkinson's schizophrenia. Evidence suggests that entrainment using sensory stimuli (GENUS) provides significant neuroprotection. This review discusses function advanced activities from both physiological pathological standpoint, it emphasizes potential therapeutic approach range neuropsychiatric diseases.

Language: Английский

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Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro

Nature Immunology, Journal Year: 2023, Volume and Issue: 24(8), P. 1382 - 1390

Published: July 27, 2023

Abstract Microglia, the macrophages of brain parenchyma, are key players in neurodegenerative diseases such as Alzheimer’s disease. These cells adopt distinct transcriptional subtypes known states. Understanding state function, especially human microglia, has been elusive owing to a lack tools model and manipulate these cells. Here, we developed platform for modeling microglia states vitro. We found that exposure stem-cell-differentiated synaptosomes, myelin debris, apoptotic neurons or synthetic amyloid-beta fibrils generated diversity mapped gene signatures identified including disease-associated enriched diseases. Using new lentiviral approach, demonstrated transcription factor MITF drives signature highly phagocytic state. Together, enable manipulation functional interrogation microglial both homeostatic disease-relevant contexts.

Language: Английский

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Landscape of human organoids: Ideal model in clinics and research

The Innovation, Journal Year: 2024, Volume and Issue: 5(3), P. 100620 - 100620

Published: April 1, 2024

In the last decade, organoid research has entered a golden era, signifying pivotal shift in biomedical landscape. The year 2023 marked milestone with publication of thousands papers this arena, reflecting exponential growth. However, amid burgeoning expansion, comprehensive and accurate overview field been conspicuously absent. Our review is intended to bridge gap, providing panoramic view rapidly evolving We meticulously analyze from eight distinctive vantage points, harnessing our rich experience academic research, industrial application, clinical practice. present deep exploration advances technology, underpinned by long-standing involvement arena. narrative traverses historical genesis organoids their transformative impact across various sectors, including oncology, toxicology, drug development. delve into synergy between avant-garde technologies such as synthetic biology single-cell omics discuss role tailoring personalized medicine, enhancing high-throughput screening, constructing physiologically pertinent disease models. analysis reflective discourse provide dive existing landscape emerging trends technology. spotlight technological innovations, methodological evolution, broadening spectrum applications, emphasizing revolutionary influence discovery, other fields. Looking ahead, we cautiously anticipate future developments especially its potential implications for patient care, new avenues research. trust that will be an asset researchers, clinicians, patients keen interest medical strategies. offer broad prospective capabilities encompassing wide range current applications. summary, attempt field. reflections, summaries, projections might useful researchers hope contribute shaping trajectory dynamic advancing

Language: Английский

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The Impact of Microglia on Neurodevelopment and Brain Function in Autism

Biomedicines, Journal Year: 2024, Volume and Issue: 12(1), P. 210 - 210

Published: Jan. 17, 2024

Microglia, as one of the main types glial cells in central nervous system (CNS), are widely distributed throughout brain and spinal cord. The normal number function microglia very important for maintaining homeostasis CNS. In recent years, scientists have paid widespread attention to role Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder, patients with ASD severe deficits behavior, social skills, communication. Most previous studies on focused neuronal pathological changes, such increased cell proliferation, accelerated differentiation, impaired synaptic development, reduced spontaneous synchronous activity. Currently, more research has found that microglia, immune cells, can promote neurogenesis pruning maintain CNS homeostasis. They usually reduce unnecessary connections early life. Some researchers proposed many phenotypes may be caused by microglial abnormalities. Based this, we summarize ASD, focusing We aim clarify essential factors influenced explore possibility microglia-related pathways potential targets ASD.

Language: Английский

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AI‐organoid integrated systems for biomedical studies and applications

Bioengineering & Translational Medicine, Journal Year: 2024, Volume and Issue: 9(2)

Published: Jan. 20, 2024

Abstract In this review, we explore the growing role of artificial intelligence (AI) in advancing biomedical applications human pluripotent stem cell (hPSC)‐derived organoids. Stem cell‐derived organoids, these miniature organ replicas, have become essential tools for disease modeling, drug discovery, and regenerative medicine. However, analyzing vast intricate datasets generated from organoids can be inefficient error‐prone. AI techniques offer a promising solution to efficiently extract insights make predictions diverse data types microscopy images, transcriptomics, metabolomics, proteomics. This review offers brief overview organoid characterization fundamental concepts while focusing on comprehensive exploration organoid‐based modeling evaluation. It provides into future possibilities enhancing quality control fabrication, label‐free recognition, three‐dimensional image reconstruction complex structures. presents challenges potential solutions AI‐organoid integration, establishment reliable model decision‐making processes standardization research.

Language: Английский

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Microglia-mediated synaptic pruning as a key deficit in neurodevelopmental disorders: Hype or hope?

Current Opinion in Neurobiology, Journal Year: 2023, Volume and Issue: 79, P. 102674 - 102674

Published: Jan. 17, 2023

There is a consensus in the field that microglia play prominent role neurodevelopmental processes like synaptic pruning and neuronal network maturation. Thus, current momentum of associating deficits with disorders (NDDs) emerged. This concept challenged by rodent studies clinical data. Intriguingly, reduced numbers or altered microglial functions do not necessarily lead to overt NDD phenotypes, neuropsychiatric symptoms seem develop primarily adulthood. Hence, it remains open for discussion whether are truly indispensable healthy neurodevelopment. Here, we critically discuss highlight area- age dependency. We propose an updated model microglia-mediated context NDDs potential targeting treatment these disorders.

Language: Английский

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