Schizophrenia endothelial cells exhibit higher permeability and altered angiogenesis patterns in patient-derived organoids DOI Creative Commons
Isidora Stanković, Michael Notaras, Paul Wolujewicz

и другие.

Translational Psychiatry, Год журнала: 2024, Номер 14(1)

Опубликована: Янв. 23, 2024

Abstract Schizophrenia (SCZ) is a complex neurodevelopmental disorder characterized by the manifestation of psychiatric symptoms in early adulthood. While many research avenues into origins SCZ during brain development have been explored, contribution endothelial/vascular dysfunction to disease remains largely elusive. To model neuropathology critical periods development, we utilized patient-derived induced pluripotent stem cells (iPSCs) generate 3D cerebral organoids and define cell-specific signatures disease. Single-cell RNA sequencing revealed that while were similar their macromolecular diversity generated from healthy controls (CTRL), exhibited higher percentage endothelial when normalized total cell numbers. Additionally, compared CTRL, differential gene expression analysis significant enrichment genes function vessel formation, vascular regulation, inflammatory response cells. In line with these findings, data 23 donors demonstrated PECAM1 + microvascular vessel-like structures increased length number comparison CTRL organoids. Furthermore, report displayed paracellular permeability, implicating elevated activity. Collectively, our identified altered patterns, structural changes, enhanced permeability models SCZ. Hence, could play role etiology modulating developing blood barrier (BBB).

Язык: Английский

Generation of vascularized brain organoids to study neurovascular interactions DOI Creative Commons

Xin-Yao Sun,

Xiang-Chun Ju, Yang Li

и другие.

eLife, Год журнала: 2022, Номер 11

Опубликована: Май 4, 2022

Brain organoids have been used to recapitulate the processes of brain development and related diseases. However, lack vasculatures, which regulate neurogenesis disorders, limits utility organoids. In this study, we induced vessel organoids, respectively, then fused two types together obtain vascularized The were engrafted with robust vascular network-like structures exhibited increased number neural progenitors, in line possibility that vessels development. Fusion also contained functional blood–brain barrier-like structures, as well microglial cells, a specific population immune cells brain. incorporated microglia responded actively stimuli showed ability engulfing synapses. Thus, fusion established study allow modeling interactions between neuronal non-neuronal components vitro, particularly vasculature niche.

Язык: Английский

Процитировано

239
The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2 DOI Creative Commons
Susanne Krasemann, Undine Haferkamp, Susanne Pfefferle

и другие.

Stem Cell Reports, Год журнала: 2022, Номер 17(2), С. 307 - 320

Опубликована: Янв. 20, 2022

Neurological complications are common in COVID-19. Although SARS-CoV-2 has been detected patients' brain tissues, its entry routes and resulting consequences not well understood. Here, we show a pronounced upregulation of interferon signaling pathways the neurovascular unit fatal By investigating susceptibility human induced pluripotent stem cell (hiPSC)-derived capillary endothelial-like cells (BCECs) to infection, found that BCECs were infected recapitulated transcriptional changes vivo. While compromised their paracellular tightness, basolateral compartment transwell assays after apical suggesting active replication transcellular transport virus across blood-brain barrier (BBB) vitro. Moreover, into could be reduced by anti-spike-, anti-angiotensin-converting enzyme 2 (ACE2)-, anti-neuropilin-1 (NRP1)-specific antibodies or transmembrane protease serine subtype (TMPRSS2) inhibitor nafamostat. Together, our data provide strong support for BBB increased signaling.

Язык: Английский

Процитировано

205
Advancing cell therapy for neurodegenerative diseases DOI Creative Commons
Sally Temple

Cell stem cell, Год журнала: 2023, Номер 30(5), С. 512 - 529

Опубликована: Апрель 20, 2023

Язык: Английский

Процитировано

98
Intrinsic blood–brain barrier dysfunction contributes to multiple sclerosis pathogenesis DOI Open Access
Hideaki Nishihara, Sylvain Perriot, Benjamin D. Gastfriend

и другие.

Brain, Год журнала: 2022, Номер 145(12), С. 4334 - 4348

Опубликована: Янв. 24, 2022

Blood-brain barrier (BBB) breakdown and immune cell infiltration into the CNS are early hallmarks of multiple sclerosis (MS). The mechanisms leading to BBB dysfunction incompletely understood generally thought be a consequence neuroinflammation. Here, we have challenged this view asked if intrinsic alterations in MS patients contribute pathogenesis. To end, made use human induced pluripotent stem cells derived from healthy controls differentiated them brain microvascular endothelial (BMEC)-like as vitro model BBB. MS-derived BMEC-like showed impaired junctional integrity, properties efflux pump activity when compared controls. Also, displayed an inflammatory phenotype with increased adhesion molecule expression interactions. Activation Wnt/β-catenin signalling progenitor enhanced characteristics reduced phenotype. Our study provides evidence for impairment function that can modelled vitro. Human iPSC-derived thus suitable explore molecular underpinnings will assist identification potential novel therapeutic targets stabilization.

Язык: Английский

Процитировано

85
The Neurovasculome: Key Roles in Brain Health and Cognitive Impairment: A Scientific Statement From the American Heart Association/American Stroke Association DOI Open Access
Costantino Iadecola, Eric E. Smith, Josef Anrather

и другие.

Stroke, Год журнала: 2023, Номер 54(6)

Опубликована: Апрель 3, 2023

Preservation of brain health has emerged as a leading public priority for the aging world population. Advances in neurovascular biology have revealed an intricate relationship among cells, meninges, and hematic lymphatic vasculature (the neurovasculome) that is highly relevant to maintenance cognitive function. In this scientific statement, multidisciplinary team experts examines these advances, assesses their relevance disease, identifies knowledge gaps, provides future directions.

Язык: Английский

Процитировано

82
The CLDN5 gene at the blood-brain barrier in health and disease DOI Creative Commons
Yosuke Hashimoto, Chris Greene, Arnold Münnich

и другие.

Fluids and Barriers of the CNS, Год журнала: 2023, Номер 20(1)

Опубликована: Март 28, 2023

Abstract The CLDN5 gene encodes claudin-5 (CLDN-5) that is expressed in endothelial cells and forms tight junctions which limit the passive diffusions of ions solutes. blood–brain barrier (BBB), composed brain microvascular associated pericytes end-feet astrocytes, a physical biological to maintain microenvironment. expression CLDN-5 tightly regulated BBB by other junctional proteins supports from astrocytes. most recent literature clearly shows compromised with decline increasing risks developing neuropsychiatric disorders, epilepsy, calcification dementia. purpose this review summarize known diseases function. In first part review, we highlight understanding how as well astrocytes cells. We detail some drugs can enhance these are being developed or currently use treat decline. then summarise mutagenesis-based studies have facilitated better physiological role protein at demonstrated functional consequences recently identified pathogenic missense mutation patients alternating hemiplegia childhood. This gain-of-function CLDN family all others representing loss-of-function mutations resulting mis-localization and/or attenuated Finally, reports about dosage-dependent effect on development neurological mice discuss what cellular for regulation human diseases.

Язык: Английский

Процитировано

68
Modeling blood-brain barrier formation and cerebral cavernous malformations in human PSC-derived organoids DOI
Lan T.M. Dao, Zhen You, Lu Lu

и другие.

Cell stem cell, Год журнала: 2024, Номер 31(6), С. 818 - 833.e11

Опубликована: Май 15, 2024

Язык: Английский

Процитировано

40
Tumor-on-chip modeling of organ-specific cancer and metastasis DOI Creative Commons
Nuala Del Piccolo, Venktesh S. Shirure, Ye Bi

и другие.

Advanced Drug Delivery Reviews, Год журнала: 2021, Номер 175, С. 113798 - 113798

Опубликована: Май 18, 2021

Every year, cancer claims millions of lives around the globe. Unfortunately, model systems that accurately mimic human oncology – a requirement for development more effective therapies these patients remain elusive. Tumor is an organ-specific process involves modification existing tissue features, recruitment other cell types, and eventual metastasis to distant organs. Recently, engineered microfluidic devices have emerged as powerful in vitro tool physiology pathology with organ-specificity. These organ-on-chip platforms consist cells cultured 3D hydrogels offer precise control over geometry, biological components, physiochemical properties. Here, we review progress towards models primary metastatic tumor microenvironments. Despite field's infancy, tumor-on-chip enabled discoveries about immunobiology response therapy. Future work should focus on autologous or multi-organ inclusion immune system.

Язык: Английский

Процитировано

87
Blood–Brain Barrier and Neurodegenerative Diseases—Modeling with iPSC-Derived Brain Cells DOI Open Access
Ying‐Chieh Wu, Tuuli-Maria Sonninen, Sanni Peltonen

и другие.

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(14), С. 7710 - 7710

Опубликована: Июль 19, 2021

The blood-brain barrier (BBB) regulates the delivery of oxygen and important nutrients to brain through active passive transport prevents neurotoxins from entering brain. It also has a clearance function removes carbon dioxide toxic metabolites central nervous system (CNS). Several drugs are unable cross BBB enter CNS, adding complexity drug screens targeting disorders. A well-functioning is essential for maintaining healthy tissue, malfunction BBB, linked its permeability, results in toxins immune cells CNS. This impairment associated with variety neurological diseases, including Alzheimer's disease Parkinson's disease. Here, we summarize current knowledge about neurodegenerative diseases. Furthermore, focus on recent progress using human-induced pluripotent stem cell (iPSC)-derived models study BBB. We review potential novel cell-based platforms modeling address advances key challenges technology human Finally, highlight future directions this area.

Язык: Английский

Процитировано

69
A microengineered Brain-Chip to model neuroinflammation in humans DOI Creative Commons
Iosif Pediaditakis, Konstantia Kodella, Dimitris V. Manatakis

и другие.

iScience, Год журнала: 2022, Номер 25(8), С. 104813 - 104813

Опубликована: Июль 21, 2022

Species differences in brain and blood-brain barrier (BBB) biology hamper the translation of findings from animal models to humans, impeding development therapeutics for diseases. Here, we present a human organotypic microphysiological system (MPS) that includes endothelial-like cells, pericytes, glia, cortical neurons maintains BBB permeability at vivo relevant levels. This Brain-Chip engineered recapitulate critical aspects complex interactions mediate neuroinflammation demonstrates significant improvements clinical mimicry compared previously reported similar MPS. In comparison Transwell culture, transcriptomic profiling displayed significantly advanced similarity adult cortex enrichment key neurobiological pathways. Exposure TNF-α recreated anticipated inflammatory environment shown by glia activation, increased release proinflammatory cytokines, compromised permeability. We report robust MPS mechanistic understanding cell-cell function during neuroinflammation.

Язык: Английский

Процитировано

54