Morphological, cellular, and molecular basis of brain infection in COVID-19 patients

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(35)

Published: Aug. 11, 2022

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum cerebral impact acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranging from alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to damage confirmed brain tissue samples extracted orbitofrontal region (via endonasal transethmoidal access) who died COVID-19. In an independent cohort 26 COVID-19, we used histopathological signs a guide for possible SARS-CoV-2 infection found that among 5 exhibited those signs, all them had genetic material virus brain. Brain these five patients also foci replication, particularly astrocytes. Supporting hypothesis astrocyte neural stem cell-derived human astrocytes vitro are susceptible through noncanonical mechanism involves spike-NRP1 interaction. SARS-CoV-2-infected manifested changes energy metabolism key proteins metabolites fuel neurons, well biogenesis neurotransmitters. Moreover, elicits secretory phenotype reduces neuronal viability. Our data support model which reaches brain, infects astrocytes, consequently, leads death or dysfunction. These deregulated processes could contribute structural functional seen brains patients.

Language: Английский

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Human brain organogenesis: Toward a cellular understanding of development and disease

Cell, Journal Year: 2021, Volume and Issue: 185(1), P. 42 - 61

Published: Nov. 11, 2021

Language: Английский

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Challenges of Organoid Research

Annual Review of Neuroscience, Journal Year: 2022, Volume and Issue: 45(1), P. 23 - 39

Published: Jan. 5, 2022

Organoids are 3D cell culture systems derived from human pluripotent stem cells that contain tissue resident types and reflect features of early organization. Neural organoids a particularly innovative scientific advance given the lack accessibility developing brain intractability neurological diseases. have become an invaluable approach to model development not well reflected in animal models. also hold promise for study atypical cellular, molecular, genetic underscore Additionally, may provide platform testing therapeutics potential source replacement approaches injury or disease. Despite promising organoids, their broad utility is tempered by variety limitations yet be overcome, including high-fidelity types, limited maturation, physiology, arealization, limit reliability certain applications.

Language: Английский

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Tropism of SARS-CoV-2 for human cortical astrocytes

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(30)

Published: July 12, 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) readily infects a variety of cell types impacting the function vital organ systems, with particularly impact on function. Neurological symptoms, which range in severity, accompany as many one-third COVID-19 cases, indicating potential vulnerability neural types. To assess whether human cortical cells can be directly infected by SARS-CoV-2, we utilized stem-cell-derived organoids well primary tissue, both from developmental and adult stages. We find significant predominant infection astrocytes tissue organoid cultures, minimal other populations. Infected bystander have corresponding increase inflammatory gene expression, reactivity characteristics, increased cytokine growth factor signaling, cellular stress. Although cells, astrocytes, no observable ACE2 high levels coreceptors including CD147 DPP4. Decreasing coreceptor abundance activity reduces overall rate, increasing expression is sufficient to promote infection. Thus, tropism SARS-CoV-2 for resulting gliosis-type injury that dependent coreceptors.

Language: Английский

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Human organoid models to study SARS-CoV-2 infection

Nature Methods, Journal Year: 2022, Volume and Issue: 19(4), P. 418 - 428

Published: April 1, 2022

Language: Английский

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COVID-19 and the Vasculature: Current Aspects and Long-Term Consequences

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 10

Published: Feb. 15, 2022

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was first identified in December 2019 as a novel respiratory pathogen and is the causative agent of Corona Virus disease (COVID-19). Early on during this pandemic, it became apparent that SARS-CoV-2 not only restricted to infecting tract, but virus also found other tissues, including vasculature. Individuals with underlying pre-existing co-morbidities like diabetes hypertension have been more prone develop severe illness fatal outcomes COVID-19. In addition, critical clinical observations made COVID-19 patients include hypercoagulation, cardiomyopathy, heart arrythmia, endothelial dysfunction, which are indicative for an involvement vasculature pathology. Hence, review summarizes impact infection details how promotes (chronic) vascular inflammation. We provide general overview SARS-CoV-2, its entry determinant Angiotensin-Converting Enzyme II (ACE2) detection extrapulmonary tissue. Further, we describe relation between cardiovascular diseases (CVD) their Clinical findings changes reviewed detail recent evidence from vitro studies susceptibility cells discussed. conclude current notions contribution events long term consequences COVID-19, known “Long-COVID-syndrome”. Altogether, our provides detailed perspectives influence

Language: Английский

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Human pluripotent-stem-cell-derived organoids for drug discovery and evaluation

Cell stem cell, Journal Year: 2023, Volume and Issue: 30(5), P. 571 - 591

Published: May 1, 2023

Human pluripotent stem cells (hPSCs) and three-dimensional organoids have ushered in a new era for disease modeling drug discovery. Over the past decade, significant progress has been deriving functional from hPSCs, which applied to recapitulate phenotypes. In addition, these advancements extended application of hPSCs screening clinical-trial safety evaluations. This review provides an overview achievements challenges using hPSC-derived conduct relevant high-throughput, high-contentscreens evaluation. These studies greatly enhanced our knowledge toolbox precision medicine.

Language: Английский

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Neuropathogenesis-on-chips for neurodegenerative diseases

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 12, 2024

Abstract Developing diagnostics and treatments for neurodegenerative diseases (NDs) is challenging due to multifactorial pathogenesis that progresses gradually. Advanced in vitro systems recapitulate patient-like pathophysiology are emerging as alternatives conventional animal-based models. In this review, we explore the interconnected pathogenic features of different types ND, discuss general strategy modelling NDs using a microfluidic chip, introduce organoid-on-a-chip next advanced relevant model. Lastly, overview how these models being applied academic industrial drug development. The integration chips, stem cells, biotechnological devices promises provide valuable insights biomedical research developing diagnostic therapeutic solutions NDs.

Language: Английский

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The SARS-CoV-2 receptor ACE2 is expressed in mouse pericytes but not endothelial cells: Implications for COVID-19 vascular research

Stem Cell Reports, Journal Year: 2022, Volume and Issue: 17(5), P. 1089 - 1104

Published: April 21, 2022

Humanized mouse models and mouse-adapted SARS-CoV-2 virus are increasingly used to study COVID-19 pathogenesis, so it is important learn where the receptor ACE2 expressed. Here we mapped expression during postnatal development in adulthood. Pericytes CNS, heart, pancreas express strongly, as do perineurial adrenal fibroblasts, whereas endothelial cells not at any location analyzed. In a number of other organs, pericytes ACE2, including lung instead expressed bronchial epithelium alveolar type II cells. The onset organ specific: already birth, brain before, heart after day 10.5. Establishing vascular localization central correctly interpret data from modeling may shed light on cause complications.

Language: Английский

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Human assembloids

Development, Journal Year: 2022, Volume and Issue: 149(20)

Published: Oct. 15, 2022

ABSTRACT Deconstructing and then reconstructing developmental processes ex vivo is crucial to understanding how organs assemble physiology can be disrupted in disease. Human 3D stem cell-derived systems, such as organoids, have facilitated this pursuit; however, they often do not capture inter-tissue or inter-lineage cellular interactions that give rise emergent tissue properties during development. Assembloids are self-organizing systems result from the integration of multiple organoids combination with missing cell types primary explants. Here, we outline concept assembloids present their applications for studying nervous system other tissues. We describe tools used probe manipulate delineate current challenges potential new approach interrogate development

Language: Английский

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