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Annual Review of Cell and Developmental... Oct 2019The vertebrate vasculature displays high organotypic specialization, with the structure and function of blood vessels catering to the specific needs of each tissue. A... (Review)
Review
The vertebrate vasculature displays high organotypic specialization, with the structure and function of blood vessels catering to the specific needs of each tissue. A unique feature of the central nervous system (CNS) vasculature is the blood-brain barrier (BBB). The BBB regulates substance influx and efflux to maintain a homeostatic environment for proper brain function. Here, we review the development and cell biology of the BBB, focusing on the cellular and molecular regulation of barrier formation and the maintenance of the BBB through adulthood. We summarize unique features of CNS endothelial cells and highlight recent progress in and general principles of barrier regulation. Finally, we illustrate why a mechanistic understanding of the development and maintenance of the BBB could provide novel therapeutic opportunities for CNS drug delivery.
Topics: Animals; Astrocytes; Basement Membrane; Biological Transport; Blood-Brain Barrier; Brain; Central Nervous System; Endothelial Cells; Homeostasis; Humans; Leukocytes; Neurovascular Coupling; Pericytes; Tight Junctions; Transcytosis; Wnt Signaling Pathway
PubMed: 31299172
DOI: 10.1146/annurev-cellbio-100617-062608 -
American Journal of Physiology. Lung... Jan 2022Both asthma and COPD are heterogeneous diseases identified by characteristic symptoms and functional abnormalities, with airway obstruction common in both diseases.... (Review)
Review
Both asthma and COPD are heterogeneous diseases identified by characteristic symptoms and functional abnormalities, with airway obstruction common in both diseases. Asthma COPD overlap (ACO) does not define a single disease but is a descriptive term for clinical use that includes several overlapping clinical phenotypes of chronic airways disease with different underlying mechanisms. This literature review was initiated to describe published studies, identify gaps in knowledge, and propose future research goals regarding the disease pathology of ACO, especially the airway remodeling changes and inflammation aspects. Airway remodeling occurs in asthma and COPD, but there are differences in the structures affected and the prime anatomic site at which they occur. Reticular basement membrane thickening and cellular infiltration with eosinophils and T-helper (CD4+) lymphocytes are prominent features of asthma. Epithelial squamous metaplasia, airway wall fibrosis, emphysema, bronchoalveolar lavage (BAL) neutrophilia, and (CD8+) T-cytotoxic lymphocyte infiltrations in the airway wall are features of COPD. There is no universally accepted definition of ACO, nor are there clearly defined pathological characteristics to differentiate from asthma and COPD. Understanding etiological concepts within the purview of inflammation and airway remodeling changes in ACO would allow better management of these patients.
Topics: Airway Remodeling; Asthma; Basement Membrane; Epithelial-Mesenchymal Transition; Humans; Pulmonary Disease, Chronic Obstructive
PubMed: 34668439
DOI: 10.1152/ajplung.00121.2021 -
German Medical Science : GMS E-journal 2022Since the era when macular hole was considered untreatable, macular hole surgery has come a long way to being one of the most successful surgeries. Internal limiting... (Review)
Review
Since the era when macular hole was considered untreatable, macular hole surgery has come a long way to being one of the most successful surgeries. Internal limiting membrane (ILM) peeling has been an essential step of macular hole surgery since the establishment of the role of ILM in the aetiopathogenesis and progression of macular hole. However, the novel technique was not all virtuous. It had some vices which were not evident immediately. With the advent of spectral domain optical coherence tomography, short- and long-term effects of ILM peeling on macular structures were known; and with microperimetry, its effect on the function of macula could be evaluated. The technique has evolved with time from total peeling to inverted flap to just temporal peeling and temporal flap in an attempt to mitigate its adverse effects and to improve its surgical outcome. ILM abrasion technique and Ocriplasmin may eliminate the need of ILM peeling in selected cases, but they have their own limitations. We here discuss the role of ILM in the pathogenesis of macular hole, the benefits and adverse effects of ILM peeling, and the various modifications of the procedure, to then explore the alternatives.
Topics: Basement Membrane; Epiretinal Membrane; Humans; Retinal Perforations; Retrospective Studies; Treatment Outcome; Visual Acuity; Vitrectomy
PubMed: 35813123
DOI: 10.3205/000309 -
Computers in Biology and Medicine Mar 2023Lung adenocarcinoma (LUAD) remains a global health concern with its poor prognosis and high mortality. Whether tumor cells invade through the basement membrane (BM) is...
BACKGROUND
Lung adenocarcinoma (LUAD) remains a global health concern with its poor prognosis and high mortality. Whether tumor cells invade through the basement membrane (BM) is the key factor to determine the prognosis of LUAD. This study aimed to identify the BM-related gene signatures to improve the overall prognosis of LUAD.
MATERIALS & METHODS
A series of bioinformatics analyses were conducted based on TCGA and GEO datasets. Unsupervised consistent cluster analysis was performed, and 500 LUAD patients were assigned to two different groups according to expressions of 222 BM-related genes. The differentially expressed genes (DEGs) between the two clusters were identified, and Lasso regression, ROC curve, univariate and multivariate Cox regression analyses and enrichment analysis were conducted. Besides, ssGSEA, CIBERSORT and ESTIMATE algorithmwere were employed to understand the relationship between the tumor microenvironment (TME) and risk scores. Moreover, single cell clustering and trajectory analyses were performed to further understand the significance of BM-related genes. Finally, qRT-PCR was used to verify the prognosis model.
RESULTS
A total of 31 prognostic BM-related genes were determined for LUAD, and a novel 17-mRNA prognostic model named BMsocre was successfully established to predict the overall survival of LUAD patients. The high BMscore group indicated worse prognosis. Seventeen DEGs were enriched mainly in metabolism, ECM-receptor interaction and immune response. In addition, the high-risk group showed higher TMB and lower immune score. The low-risk group had a better immunotherapeutic response where immune escape was less likely. The BMscore model was verified in our patient cohort. Furthermore, NELL2 was mainly expressed in clusters of T cells, and was identified to play a critical role in T-cell differentiation.
CONCLUSIONS
A novel BMscore model was successfully established and might be effective for providing guidance to LUAD therapy.
Topics: Humans; Adenocarcinoma of Lung; Basement Membrane; Cell Differentiation; Cluster Analysis; Lung Neoplasms; Tumor Microenvironment
PubMed: 36708655
DOI: 10.1016/j.compbiomed.2023.106597 -
Science (New York, N.Y.) Oct 2022We engineered an ultrasensitive reporter of , a biomarker of cellular senescence. Our reporter detected -expressing fibroblasts with certain senescent characteristics...
We engineered an ultrasensitive reporter of , a biomarker of cellular senescence. Our reporter detected -expressing fibroblasts with certain senescent characteristics that appeared shortly after birth in the basement membrane adjacent to epithelial stem cells in the lung. Furthermore, these fibroblasts had enhanced capacity to sense tissue inflammation and respond through their increased secretory capacity to promote epithelial regeneration. In addition, expression was required in fibroblasts to enhance epithelial regeneration. This study highlights a role for fibroblasts as tissue-resident sentinels in the stem cell niche that monitor barrier integrity and rapidly respond to inflammation to promote tissue regeneration.
Topics: Humans; Basement Membrane; Biomarkers; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p16; Fibroblasts; Inflammation; Lung; Genes, Reporter; Regeneration; Epithelial Cells; Stem Cell Niche
PubMed: 36227993
DOI: 10.1126/science.abf3326 -
Cell Jul 2021Many embryonic organs undergo epithelial morphogenesis to form tree-like hierarchical structures. However, it remains unclear what drives the budding and branching of...
Many embryonic organs undergo epithelial morphogenesis to form tree-like hierarchical structures. However, it remains unclear what drives the budding and branching of stratified epithelia, such as in the embryonic salivary gland and pancreas. Here, we performed live-organ imaging of mouse embryonic salivary glands at single-cell resolution to reveal that budding morphogenesis is driven by expansion and folding of a distinct epithelial surface cell sheet characterized by strong cell-matrix adhesions and weak cell-cell adhesions. Profiling of single-cell transcriptomes of this epithelium revealed spatial patterns of transcription underlying these cell adhesion differences. We then synthetically reconstituted budding morphogenesis by experimentally suppressing E-cadherin expression and inducing basement membrane formation in 3D spheroid cultures of engineered cells, which required β1-integrin-mediated cell-matrix adhesion for successful budding. Thus, stratified epithelial budding, the key first step of branching morphogenesis, is driven by an overall combination of strong cell-matrix adhesion and weak cell-cell adhesion by peripheral epithelial cells.
Topics: Animals; Basement Membrane; Cell Adhesion; Cell Division; Cell Movement; Cell Tracking; Cell-Matrix Junctions; Embryo, Mammalian; Epithelial Cells; Epithelium; Gene Expression Regulation, Developmental; HEK293 Cells; Humans; Integrins; Mice; Models, Biological; Morphogenesis; Salivary Glands; Transcriptome
PubMed: 34133940
DOI: 10.1016/j.cell.2021.05.015 -
International Journal of Biological... 2023Therapeutic failure in breast cancer patients is largely attributed to postoperative advancement and therapy resistance. Nevertheless, an efficacious prognostic...
Therapeutic failure in breast cancer patients is largely attributed to postoperative advancement and therapy resistance. Nevertheless, an efficacious prognostic signature for recognizing this population is lacking. The basement membrane (BM) has been proven to be strongly involved in cancer progression and metastasis, and has the potential to be a powerful predictor in breast cancer. In this study, substantial bulk RNA transcriptomics, single cell RNA transcriptomics and clinical information were collected from TCGA-BRCA, METABRIC and GSE96058, and Kaplan-Meier survival curves, single cell analysis and experiments were conducted to validate the signature. From the results, a prognostic index, namely, the BMscore, was established with six pivotal BM genes, specifically LOXL1, FBLN1, FBLN5, SDC1, ADAMTS8 and PXDNL. Verification by independent cohorts showed that breast cancer patients with high BMscore had a distinctly worse outcome. By integrating the BMscore and clinical factors, we constructed a prognostic nomogram that displayed good predictive capability. Furthermore, we evaluated the implication of the BMscore in breast cancer immune infiltration. More importantly, a strongly positive correlation between the BMscore and EMT activity was revealed with immunohistochemistry and experiments. Taken together, we provided a novel BMscore gene signature for breast cancer patients to predict clinical prognosis and metastasis accurately, which may help with individualized clinical decision-making.
Topics: Humans; Female; Breast Neoplasms; Basement Membrane; Gene Expression Profiling; Kaplan-Meier Estimate; Nomograms; ADAMTS Proteins
PubMed: 37056938
DOI: 10.7150/ijbs.81939 -
International Journal of Molecular... Dec 2019The dermal-epidermal junction (DEJ) provides a physical and biological interface between the epidermis and the dermis. In addition to providing a structural integrity,...
The dermal-epidermal junction (DEJ) provides a physical and biological interface between the epidermis and the dermis. In addition to providing a structural integrity, the DEJ also acts as a passageway for molecular transport. Based on the recently reported importance of the DEJ in skin aging, novel peptide derivatives have been tested for their effects on basement membrane (BM) protein expressions in cultured human epidermal keratinocytes. As a result, protein expressions of collagen XVII, laminin and nidogen were stimulated by the test peptide and peptides complex. Further ex vivo evaluation using excised human skin, confirmed that the topical application of the peptides complex significantly increased dermal collagen expression, as well as expressions of collagen XVII and laminin. Interestingly, while the origin of the laminin protein is epidermal keratinocytes, the immunohistochemical staining of skin showed that laminin was only detected in the uppermost layer of the dermis, which suggests a tight assembly of laminin protein onto the dermal side of the DEJ. These results suggest that a peptide complex could improve the structural properties of the DEJ through its ability to stimulate BM proteins. In order to evaluate the anti-wrinkle benefits of the peptide complex in vivo, a clinical study was performed on 22 healthy Asian female volunteers older than 40 years. As a result, significant improvements in skin wrinkles for all of the five sites were observed after two weeks, as assessed by skin topographic measurements. Collectively, these results demonstrate the anti-aging efficacy of the peptides complex.
Topics: Adult; Autoantigens; Basement Membrane; Cell Line; Collagen Type I; Female; Humans; Keratinocytes; Laminin; Middle Aged; Non-Fibrillar Collagens; Peptides; Skin; Skin Aging; Collagen Type XVII
PubMed: 31861912
DOI: 10.3390/ijms21010073 -
Journal of the American Society of... Apr 2022The prognosis for kidney survival is poor in patients presenting with circulating anti-glomerular basement membrane (GBM) antibodies and severe kidney injury. It is...
BACKGROUND
The prognosis for kidney survival is poor in patients presenting with circulating anti-glomerular basement membrane (GBM) antibodies and severe kidney injury. It is unknown if treatment with an endopeptidase that cleaves circulating and kidney bound IgG can alter the prognosis.
METHODS
An investigator-driven phase 2a one-arm study (EudraCT 2016-004082-39) was performed in 17 hospitals in five European countries. A single dose of 0.25 mg/kg of imlifidase was given to 15 adults with circulating anti-GBM antibodies and an eGFR <15 ml/min per 1.73m. All patients received standard treatment with cyclophosphamide and corticosteroids, but plasma exchange only if autoantibodies rebounded. The primary outcomes were safety and dialysis independency at 6 months.
RESULTS
At inclusion, ten patients were dialysis dependent and the other five had eGFR levels between 7 and 14 ml/min per 1.73m. The median age was 61 years (range 19-77), six were women, and six were also positive for anti-neutrophil cytoplasmic antibodies. Then 6 hours after imlifidase infusion, all patients had anti-GBM antibodies levels below the reference range of a prespecified assay. At 6 months 67% (ten out of 15) were dialysis independent. This is significantly higher compared with 18% (nine out of 50) in a historical control cohort (<0.001, Fisher's exact test). Eight serious adverse events (including one death) were reported, none assessed as probably or possibly related to the study drug.
CONCLUSIONS
In this pilot study, the use of imlifidase was associated with a better outcome compared with earlier publications, without major safety issues, but the findings need to be confirmed in a randomized controlled trial. EUDRACT 2016-004082-39 https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-001377-28/results.
Topics: Adult; Aged; Anti-Glomerular Basement Membrane Disease; Autoantibodies; Basement Membrane; Endopeptidases; Female; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Pilot Projects; Young Adult
PubMed: 35260419
DOI: 10.1681/ASN.2021111460 -
Molecular Neurodegeneration Dec 2021Neurodegenerative disorders are a group of age-associated diseases characterized by progressive degeneration of the structure and function of the CNS. Two key... (Review)
Review
BACKGROUND
Neurodegenerative disorders are a group of age-associated diseases characterized by progressive degeneration of the structure and function of the CNS. Two key pathological features of these disorders are blood-brain barrier (BBB) breakdown and protein aggregation.
MAIN BODY
The BBB is composed of various cell types and a non-cellular component---the basal lamina (BL). Although how different cells affect the BBB is well studied, the roles of the BL in BBB maintenance and function remain largely unknown. In addition, located in the perivascular space, the BL is also speculated to regulate protein clearance via the meningeal lymphatic/glymphatic system. Recent studies from our laboratory and others have shown that the BL actively regulates BBB integrity and meningeal lymphatic/glymphatic function in both physiological and pathological conditions, suggesting that it may play an important role in the pathogenesis and/or progression of neurodegenerative disorders. In this review, we focus on changes of the BL and its major components during aging and in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). First, we introduce the vascular and lymphatic systems in the CNS. Next, we discuss the BL and its major components under homeostatic conditions, and summarize their changes during aging and in AD, PD, and ALS in both rodents and humans. The functional significance of these alterations and potential therapeutic targets are also reviewed. Finally, key challenges in the field and future directions are discussed.
CONCLUSIONS
Understanding BL changes and the functional significance of these changes in neurodegenerative disorders will fill the gap of knowledge in the field. Our goal is to provide a clear and concise review of the complex relationship between the BL and neurodegenerative disorders to stimulate new hypotheses and further research in this field.
Topics: Alzheimer Disease; Basement Membrane; Blood-Brain Barrier; Glymphatic System; Humans; Neurodegenerative Diseases
PubMed: 34876200
DOI: 10.1186/s13024-021-00502-y