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Nature Jan 2019The increasing prevalence of diabetes has resulted in a global epidemic. Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and amputation of...
The increasing prevalence of diabetes has resulted in a global epidemic. Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and amputation of lower limbs. These are often caused by changes in blood vessels, such as the expansion of the basement membrane and a loss of vascular cells. Diabetes also impairs the functions of endothelial cells and disturbs the communication between endothelial cells and pericytes. How dysfunction of endothelial cells and/or pericytes leads to diabetic vasculopathy remains largely unknown. Here we report the development of self-organizing three-dimensional human blood vessel organoids from pluripotent stem cells. These human blood vessel organoids contain endothelial cells and pericytes that self-assemble into capillary networks that are enveloped by a basement membrane. Human blood vessel organoids transplanted into mice form a stable, perfused vascular tree, including arteries, arterioles and venules. Exposure of blood vessel organoids to hyperglycaemia and inflammatory cytokines in vitro induces thickening of the vascular basement membrane. Human blood vessels, exposed in vivo to a diabetic milieu in mice, also mimic the microvascular changes found in patients with diabetes. DLL4 and NOTCH3 were identified as key drivers of diabetic vasculopathy in human blood vessels. Therefore, organoids derived from human stem cells faithfully recapitulate the structure and function of human blood vessels and are amenable systems for modelling and identifying the regulators of diabetic vasculopathy, a disease that affects hundreds of millions of patients worldwide.
Topics: Adaptor Proteins, Signal Transducing; Amyloid Precursor Protein Secretases; Animals; Arteries; Arterioles; Basement Membrane; Blood Vessels; Calcium-Binding Proteins; Diabetic Angiopathies; Endothelial Cells; Humans; Hyperglycemia; In Vitro Techniques; Inflammation Mediators; Intercellular Signaling Peptides and Proteins; Mice; Models, Biological; Organoids; Pericytes; Pluripotent Stem Cells; Receptor, Notch3; Signal Transduction; Venules
PubMed: 30651639
DOI: 10.1038/s41586-018-0858-8 -
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 -
International Journal of Molecular... May 2016Melasma is a commonly acquired hypermelanosis that affects sun-exposed areas of the skin, with frequent facial involvement. Its histologic manifestations are evident in... (Review)
Review
Melasma is a commonly acquired hypermelanosis that affects sun-exposed areas of the skin, with frequent facial involvement. Its histologic manifestations are evident in the epidermis, extracellular matrix, and dermis. In addition to epidermal pigmentation, pathologic findings of melasma include extracellular matrix abnormality, especially solar elastosis. The disrupted basement membrane has been described in melasma with variable incidences. In the dermis, an increase in vascularity and an increase in the number of mast cells were observed, indicating that dermal factors have critical roles in the pathogenesis of melasma, despite the fact that melasma is characterized by epidermal hyperpigmentation. This review discusses such histologic characteristics of melasma, with consideration to their implications for melasma treatment.
Topics: Administration, Topical; Antioxidants; Basement Membrane; Chloroquine; Dermis; Disease Management; Gene Expression Regulation; Humans; Hydroquinones; Laser Therapy; Mast Cells; Melanosis; Phototherapy
PubMed: 27240341
DOI: 10.3390/ijms17060824 -
Nature Reviews. Molecular Cell Biology Dec 2014The biochemical and biophysical properties of the extracellular matrix (ECM) dictate tissue-specific cell behaviour. The molecules that are associated with the ECM of... (Review)
Review
The biochemical and biophysical properties of the extracellular matrix (ECM) dictate tissue-specific cell behaviour. The molecules that are associated with the ECM of each tissue, including collagens, proteoglycans, laminins and fibronectin, and the manner in which they are assembled determine the structure and the organization of the resultant ECM. The product is a specific ECM signature that is comprised of unique compositional and topographical features that both reflect and facilitate the functional requirements of the tissue.
Topics: Animals; Basement Membrane; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Neurons; Proteoglycans
PubMed: 25370693
DOI: 10.1038/nrm3902 -
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 -
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 -
Nature Biotechnology Apr 2018Age-related macular degeneration (AMD) remains a major cause of blindness, with dysfunction and loss of retinal pigment epithelium (RPE) central to disease progression....
Age-related macular degeneration (AMD) remains a major cause of blindness, with dysfunction and loss of retinal pigment epithelium (RPE) central to disease progression. We engineered an RPE patch comprising a fully differentiated, human embryonic stem cell (hESC)-derived RPE monolayer on a coated, synthetic basement membrane. We delivered the patch, using a purpose-designed microsurgical tool, into the subretinal space of one eye in each of two patients with severe exudative AMD. Primary endpoints were incidence and severity of adverse events and proportion of subjects with improved best-corrected visual acuity of 15 letters or more. We report successful delivery and survival of the RPE patch by biomicroscopy and optical coherence tomography, and a visual acuity gain of 29 and 21 letters in the two patients, respectively, over 12 months. Only local immunosuppression was used long-term. We also present the preclinical surgical, cell safety and tumorigenicity studies leading to trial approval. This work supports the feasibility and safety of hESC-RPE patch transplantation as a regenerative strategy for AMD.
Topics: Aged; Animals; Basement Membrane; Cell Differentiation; Female; Human Embryonic Stem Cells; Humans; Macular Degeneration; Male; Mice; Middle Aged; Retinal Pigment Epithelium; Stem Cell Transplantation; Swine; Tomography, Optical Coherence; Visual Acuity
PubMed: 29553577
DOI: 10.1038/nbt.4114 -
Journal of Anatomy Apr 2019Recreating the structure of human tissues in the laboratory is valuable for fundamental research, testing interventions, and reducing the use of animals. Critical to the...
Recreating the structure of human tissues in the laboratory is valuable for fundamental research, testing interventions, and reducing the use of animals. Critical to the use of such technology is the ability to produce tissue models that accurately reproduce the microanatomy of the native tissue. Current artificial cell-based skin systems lack thorough characterisation, are not representative of human skin, and can show variation. In this study, we have developed a novel full thickness model of human skin comprised of epidermal and dermal compartments. Using an inert porous scaffold, we created a dermal construct using human fibroblasts that secrete their own extracellular matrix proteins, which avoids the use of animal-derived materials. The dermal construct acts as a foundation upon which epidermal keratinocytes were seeded and differentiated into a stratified keratinised epithelium. In-depth morphological analyses of the model demonstrated very close similarities with native human skin. Extensive immunostaining and electron microscopy analysis revealed ultrastructural details such as keratohyalin granules and lamellar bodies within the stratum granulosum, specialised junctional complexes, and the presence of a basal lamina. These features reflect the functional characteristics and barrier properties of the skin equivalent. Robustness and reproducibility of in vitro models are important attributes in experimental practice, and we demonstrate the consistency of the skin construct between different users. In summary, a new model of full thickness human skin has been developed that possesses microanatomical features reminiscent of native tissue. This skin model platform will be of significant interest to scientists researching the structure and function of human skin.
Topics: Basement Membrane; Cell Differentiation; Cells, Cultured; Dermis; Epidermis; Extracellular Matrix Proteins; Fibroblasts; Humans; In Vitro Techniques; Keratinocytes; Microscopy, Electron; Skin; Tissue Engineering
PubMed: 30740672
DOI: 10.1111/joa.12942 -
Stroke and Vascular Neurology Jul 2019The blood-brain barrier (BBB) is a highly complex and dynamic structure, mainly composed of brain microvascular endothelial cells, pericytes, astrocytes and the basement... (Review)
Review
The blood-brain barrier (BBB) is a highly complex and dynamic structure, mainly composed of brain microvascular endothelial cells, pericytes, astrocytes and the basement membrane (BM). The vast majority of BBB research focuses on its cellular constituents. Its non-cellular component, the BM, on the other hand, is largely understudied due to its intrinsic complexity and the lack of research tools. In this review, we focus on the role of the BM in BBB integrity. We first briefly introduce the biochemical composition and structure of the BM. Next, the biological functions of major components of the BM in BBB formation and maintenance are discussed. Our goal is to provide a concise overview on how the BM contributes to BBB integrity.
Topics: Animals; Basement Membrane; Blood-Brain Barrier; Capillary Permeability; Collagen Type IV; Extracellular Matrix Proteins; Heparan Sulfate Proteoglycans; Humans; Laminin; Membrane Glycoproteins; Signal Transduction
PubMed: 31338215
DOI: 10.1136/svn-2018-000198 -
Essays in Biochemistry Sep 2019Basement membranes (BMs) are specialised extracellular matrix (ECM) structures and collagens are a key component required for BM function. While collagen IV is the major... (Review)
Review
Basement membranes (BMs) are specialised extracellular matrix (ECM) structures and collagens are a key component required for BM function. While collagen IV is the major BM collagen, collagens VI, VII, XV, XVII and XVIII are also present. Mutations in these collagens cause rare multi-systemic diseases but these collagens have also been associated with major common diseases including stroke. Developing treatments for these conditions will require a collective effort to increase our fundamental understanding of the biology of these collagens and the mechanisms by which mutations therein cause disease. Novel insights into pathomolecular disease mechanisms and cellular responses to these mutations has been exploited to develop proof-of-concept treatment strategies in animal models. Combined, these studies have also highlighted the complexity of the disease mechanisms and the need to obtain a more complete understanding of these mechanisms. The identification of pathomolecular mechanisms of collagen mutations shared between different disorders represent an attractive prospect for treatments that may be effective across phenotypically distinct disorders.
Topics: Animals; Basement Membrane; Collagen Diseases; Genetic Therapy; Humans; Mutation; Non-Fibrillar Collagens
PubMed: 31387942
DOI: 10.1042/EBC20180071