ABSTRACT
Blood-brain barrier (BBB) dysfunction is emerging as a key pathogenic factor in the progression of Alzheimer's disease (AD), where increased microvascular endothelial permeability has been proposed to play an important role. However, the molecular mechanisms leading to increased brain microvascular permeability in AD are not fully understood. We studied brain endothelial permeability in female APPswe/PS1∆E9 (APP/PS1) mice which constitute a transgenic mouse model of amyloid-beta (Aß) amyloidosis and found that permeability increases with aging in the areas showing the greatest amyloid plaque deposition. We performed an unbiased bulk RNA-sequencing analysis of brain endothelial cells (BECs) in female APP/PS1 transgenic mice. We observed that upregulation of interferon signaling gene expression pathways in BECs was among the most prominent transcriptomic signatures in the brain endothelium. Immunofluorescence analysis of isolated BECs from female APP/PS1 mice demonstrated higher levels of the Type I interferon-stimulated gene IFIT2. Immunoblotting of APP/PS1 BECs showed downregulation of the adherens junction protein VE-cadherin. Stimulation of human brain endothelial cells with interferon-ß decreased the levels of the adherens junction protein VE-cadherin as well as tight junction proteins Occludin and Claudin-5 and increased barrier leakiness. Depletion of the Type I interferon receptor in human brain endothelial cells prevented interferon-ß-induced VE-cadherin downregulation and restored endothelial barrier integrity. Our study suggests that Type I interferon signaling contributes to brain endothelial dysfunction in AD.
Subject(s)
Alzheimer Disease , Interferon Type I , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Animals , Blood-Brain Barrier/metabolism , Brain/metabolism , Claudin-5/metabolism , Disease Models, Animal , Endothelial Cells/metabolism , Endothelium/metabolism , Female , Humans , Interferon Type I/metabolism , Interferon-beta/metabolism , Mice , Mice, Transgenic , Occludin/metabolism , Plaque, Amyloid/pathology , RNA/metabolism , Receptor, Interferon alpha-beta/metabolism , Tight Junction Proteins/metabolismABSTRACT
Macrophages demonstrate remarkable plasticity that is essential for host defense and tissue repair. The tissue niche imprints macrophage identity, phenotype and function. The role of vascular endothelial signals in tailoring the phenotype and function of tissue macrophages remains unknown. The lung is a highly vascularized organ and replete with a large population of resident macrophages. We found that, in response to inflammatory injury, lung endothelial cells release the Wnt signaling modulator Rspondin3, which activates ß-catenin signaling in lung interstitial macrophages and increases mitochondrial respiration by glutaminolysis. The generated tricarboxylic acid cycle intermediate α-ketoglutarate, in turn, serves as the cofactor for the epigenetic regulator TET2 to catalyze DNA hydroxymethylation. Notably, endothelial-specific deletion of Rspondin3 prevented the formation of anti-inflammatory interstitial macrophages in endotoxemic mice and induced unchecked severe inflammatory injury. Thus, the angiocrine-metabolic-epigenetic signaling axis specified by the endothelium is essential for reprogramming interstitial macrophages and dampening inflammatory injury.
Subject(s)
Cellular Reprogramming , Energy Metabolism , Epigenesis, Genetic , Inflammation/etiology , Inflammation/metabolism , Macrophages/immunology , Macrophages/metabolism , Thrombospondins/genetics , Animals , Biomarkers , Cellular Reprogramming/genetics , Cellular Reprogramming/immunology , Disease Models, Animal , Disease Susceptibility , Fluorescent Antibody Technique , Inflammation/pathology , Mice , Mice, Knockout , Mice, Transgenic , Thrombospondins/metabolismABSTRACT
Cardiac stem/progenitors are being used in the clinic to treat patients with a range of cardiac pathologies. However, improvements in heart function following treatment have been reported to be variable, with some showing no response. This discrepancy in response remains unresolved. Mesenchymal stem cells (MSCs) have been highlighted as a regenerative tool as these cells display both immunomodulatory and proregenerative activities. The purpose of this study was to derive a cardiac MSC population to provide an alternative/support to current therapies. We derived human cardiac-mesenchymal stem cell-like cells (CMSCLC), so named as they share some MSC characteristics. However, CMSCLC lack the MSC trilineage differentiation capacity, being capable of only rare adipogenic differentiation and demonstrating low/no osteogenic or chondrogenic potential, a phenotype that may have advantages following transplantation. Furthermore, CMSCLC expressed low levels of p16, high levels of MHCI, and low levels of MHCII. A lack of senescent cells would also be advantageous for cells to be used therapeutically, as would the ability to modulate the immune response. Crucially, CMSCLC display a transcriptional profile that includes genes associated with cardioprotective/cardiobeneficial effects. CMSCLC are also secretory and multipotent, giving rise to cardiomyocytes and endothelial cells. Our findings support CMSCLC as a novel cell population suitable for use for transplantation.
