Dataset Information

Astrocyte-Derived TGF?1 Facilitates Blood-Brain Barrier Function via Non-Canonical Hedgehog Signaling in Brain Microvascular Endothelial Cells.

ABSTRACT: The blood-brain barrier is a specialized structure in mammals, separating the brain from the bloodstream and maintaining the homeostasis of the central nervous system. The barrier is composed of various types of cells, and the communication between these cells is critical to blood-brain barrier (BBB) function. Here, we demonstrate the astrocyte-derived TGF?1-mediated intercellular communication between astrocytes and brain microvascular endothelial cells (BMECs). By using an in vitro co-culture model, we observed that the astrocyte-derived TGF?1 enhanced the tight junction protein ZO-1 expression in BMECs and the endothelial barrier function via a non-canonical hedgehog signaling. Gli2, the core transcriptional factor of the hedgehog pathway, was demonstrated to modulate ZO-1 expression directly. By the dual-luciferase reporter system and chromatin immunoprecipitation, we further identified the exact sites on Smad2/3 that bound to the gli2 promotor and on Gli2 that bound to the zo-1 promotor. Our work highlighted the TGF?1-mediated intercellular communication of astrocytes with BMECs in BBB, which shall extend current knowledge on the BBB homeostasis physiologically, and more importantly suggests TGF?1 as a potential effector for future prevention and amelioration of BBB dysfunction.

SUBMITTER: Fu J

PROVIDER: S-EPMC7826596 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Astrocyte-Derived TGFβ1 Facilitates Blood-Brain Barrier Function via Non-Canonical Hedgehog Signaling in Brain Microvascular Endothelial Cells.

Fu Jiyang J Li Liang L Huo Dong D Zhi Shuli S Yang Ruicheng R Yang Bo B Xu Bojie B Zhang Tao T Dai Menghong M Tan Chen C Chen Huanchun H Wang Xiangru X

Brain sciences 20210108 1

The blood-brain barrier is a specialized structure in mammals, separating the brain from the bloodstream and maintaining the homeostasis of the central nervous system. The barrier is composed of various types of cells, and the communication between these cells is critical to blood-brain barrier (BBB) function. Here, we demonstrate the astrocyte-derived TGFβ1-mediated intercellular communication between astrocytes and brain microvascular endothelial cells (BMECs). By using an in vitro co-culture ...[more]

PMID: 33430164

Similar Datasets

Project description:Japanese encephalitis virus (JEV) remains a leading cause of encephalitis, globally, which continues to grow in importance despite the availability of vaccines. Viral entry into the brain can occur via the blood-brain barrier (BBB), and inflammation at the BBB is a common final pathway in many brain infections. However, the role of the BBB during JEV infection and the contribution of the endothelial and astrocytic cell inflammation in facilitating virus entry into the brain are incompletely understood. We established a BBB model using human brain endothelial cells (HBECs) and human astrocytes. HBECs are polarised, and therefore the model was inoculated by JEV from the apical side to simulate the in vivo situation. The effects of JEV on the BBB permeability and release of inflammatory mediators from both apical and basolateral sides, representing the blood and the brain side respectively were investigated. JEV infected HBECs with limited active virus production, before crossing the BBB and infecting astrocytes. Control of JEV production by HBECs was associated with a significant increase in permeability, and with elevation of many host mediators, including cytokines, chemokines, cellular adhesion molecules, and matrix metalloproteases. When compared to the controls, significantly higher amounts of mediators were released from the apical side as opposed to the basolateral side. The increased release of mediators over time also correlated with increased BBB permeability. Treatment with dexamethasone led to a significant reduction in the release of interleukin 6 (IL6), C-C motif chemokine ligand 5 (CCL5) and C-X-C motif chemokine ligand 10 (CXCL10) from the apical side with a reduction in BBB disruption and no change in JEV production. The results are consistent with the hypothesis that JEV infection of the BBB triggers the production of a range of host mediators from both endothelial cells and astrocytes, which control JEV production but disrupt BBB integrity thus allowing virus entry into the brain. Dexamethasone treatment controlled the host response and limited BBB disruption in the model without increasing JEV production, supporting a re-investigation of its use therapeutically.

Project description:Autoreactive T lymphocytes crossing the blood-brain barrier (BBB) into the central nervous system (CNS) play a crucial role in the initiation of demyelination and neurodegeneration in multiple sclerosis (MS). Recently, extracellular vesicles (EV) secreted by BBB endothelial cells (BBB-EC) have emerged as a unique form of cell-to-cell communication that contributes to cerebrovascular dysfunction. However, the precise impact of different size-based subpopulations of BBB-EC-derived EV (BBB-EV) on the early stages of MS remains unclear. Therefore, our objective was to investigate the content and function of distinct BBB-EV subpopulations in regulating BBB integrity and their role in T cell transendothelial migration, both in vitro and in vivo. Our study reveals that BBB-ECs release two distinct size based EV populations, namely small EV (sEV; 30-150 nm) and large EV (lEV; 150-300 nm), with a significantly higher secretion of sEV during inflammation. Notably, the expression patterns of cytokines and adhesion markers differ significantly between these BBB-EV subsets, indicating specific functional differences in the regulation of T cell migration. Through in vitro experiments, we demonstrate that lEV, which predominantly reflect their cellular source, play a major role in BBB integrity loss and the enhanced migration of pro-inflammatory Th1 and Th17.1 cells. Conversely, sEV appear to protect BBB function by inducing an anti-inflammatory phenotype in BBB-EC. These findings align with our in vivo data, where the administration of sEV to mice with experimental autoimmune encephalomyelitis (EAE) results in lower disease severity compared to the administration of lEV, which exacerbates disease symptoms. In conclusion, our study highlights the distinct and opposing effects of BBB-EV subpopulations on the BBB, both in vitro and in vivo. These findings underscore the need for further investigation into the diagnostic and therapeutic potential of BBB-EV in the context of MS.

Dataset Information

Astrocyte-Derived TGF?1 Facilitates Blood-Brain Barrier Function via Non-Canonical Hedgehog Signaling in Brain Microvascular Endothelial Cells.

Publications

Astrocyte-Derived TGFβ1 Facilitates Blood-Brain Barrier Function via Non-Canonical Hedgehog Signaling in Brain Microvascular Endothelial Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets