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Matrix Biology : Journal of the... Sep 2015The LTBPs (or latent transforming growth factor β binding proteins) are important components of the extracellular matrix (ECM) that interact with fibrillin microfibrils... (Review)
Review
The LTBPs (or latent transforming growth factor β binding proteins) are important components of the extracellular matrix (ECM) that interact with fibrillin microfibrils and have a number of different roles in microfibril biology. There are four LTBPs isoforms in the human genome (LTBP-1, -2, -3, and -4), all of which appear to associate with fibrillin and the biology of each isoform is reviewed here. The LTBPs were first identified as forming latent complexes with TGFβ by covalently binding the TGFβ propeptide (LAP) via disulfide bonds in the endoplasmic reticulum. LAP in turn is cleaved from the mature TGFβ precursor in the trans-golgi network but LAP and TGFβ remain strongly bound through non-covalent interactions. LAP, TGFβ, and LTBP together form the large latent complex (LLC). LTBPs were originally thought to primarily play a role in maintaining TGFβ latency and targeting the latent growth factor to the extracellular matrix (ECM), but it has also been shown that LTBP-1 participates in TGFβ activation by integrins and may also regulate activation by proteases and other factors. LTBP-3 appears to have a role in skeletal formation including tooth development. As well as having important functions in TGFβ regulation, TGFβ-independent activities have recently been identified for LTBP-2 and LTBP-4 in stabilizing microfibril bundles and regulating elastic fiber assembly.
Topics: Animals; Extracellular Matrix; Fibrillins; Humans; Latent TGF-beta Binding Proteins; Microfilament Proteins; Protein Isoforms; Signal Transduction; Transforming Growth Factor beta
PubMed: 25960419
DOI: 10.1016/j.matbio.2015.05.005 -
Gene Oct 2016FBN1 encodes the gene for fibrillin-1, a structural macromolecule that polymerizes into microfibrils. Fibrillin microfibrils are morphologically distinctive fibrils,... (Review)
Review
FBN1 encodes the gene for fibrillin-1, a structural macromolecule that polymerizes into microfibrils. Fibrillin microfibrils are morphologically distinctive fibrils, present in all connective tissues and assembled into tissue-specific architectural frameworks. FBN1 is the causative gene for Marfan syndrome, an inherited disorder of connective tissue whose major features include tall stature and arachnodactyly, ectopia lentis, and thoracic aortic aneurysm and dissection. More than one thousand individual mutations in FBN1 are associated with Marfan syndrome, making genotype-phenotype correlations difficult. Moreover, mutations in specific regions of FBN1 can result in the opposite features of short stature and brachydactyly characteristic of Weill-Marchesani syndrome and other acromelic dysplasias. How can mutations in one molecule result in disparate clinical syndromes? Current concepts of the fibrillinopathies require an appreciation of tissue-specific fibrillin microfibril microenvironments and the collaborative relationship between the structures of fibrillin microfibril networks and biological functions such as regulation of growth factor signaling.
Topics: Animals; Disease Models, Animal; Fibrillin-1; Genetic Predisposition to Disease; Humans; Marfan Syndrome; Mutation
PubMed: 27437668
DOI: 10.1016/j.gene.2016.07.033 -
Frontiers in Aging Neuroscience 2016Tendons among connective tissue, mainly collagen, contain also elastic fibers (EF) made of fibrillin 1, fibrillin 2 and elastin that are broadly distributed in tendons... (Review)
Review
Tendons among connective tissue, mainly collagen, contain also elastic fibers (EF) made of fibrillin 1, fibrillin 2 and elastin that are broadly distributed in tendons and represent 1-2% of the dried mass of the tendon. Only in the last years, studies on structure and function of EF in tendons have been performed. Aim of this review is to revise data on the organization of EF in tendons, in particular fibrillin structure and function, and on the clinical manifestations associated to alterations of EF in tendons. Indeed, microfibrils may contribute to tendon mechanics; therefore, their alterations may cause joint hypermobility and contractures which have been found to be clinical features in patients with Marfan syndrome (MFS) and Beals syndrome. The two diseases are caused by mutations in genes FBN1 and FBN2 encoding fibrillin 1 and fibrillin 2, respectively.
PubMed: 27812333
DOI: 10.3389/fnagi.2016.00237 -
Biomaterials Dec 2016Engineering cardiac tissues and organ models remains a great challenge due to the hierarchical structure of the native myocardium. The need of integrating blood vessels...
Engineering cardiac tissues and organ models remains a great challenge due to the hierarchical structure of the native myocardium. The need of integrating blood vessels brings additional complexity, limiting the available approaches that are suitable to produce integrated cardiovascular organoids. In this work we propose a novel hybrid strategy based on 3D bioprinting, to fabricate endothelialized myocardium. Enabled by the use of our composite bioink, endothelial cells directly bioprinted within microfibrous hydrogel scaffolds gradually migrated towards the peripheries of the microfibers to form a layer of confluent endothelium. Together with controlled anisotropy, this 3D endothelial bed was then seeded with cardiomyocytes to generate aligned myocardium capable of spontaneous and synchronous contraction. We further embedded the organoids into a specially designed microfluidic perfusion bioreactor to complete the endothelialized-myocardium-on-a-chip platform for cardiovascular toxicity evaluation. Finally, we demonstrated that such a technique could be translated to human cardiomyocytes derived from induced pluripotent stem cells to construct endothelialized human myocardium. We believe that our method for generation of endothelialized organoids fabricated through an innovative 3D bioprinting technology may find widespread applications in regenerative medicine, drug screening, and potentially disease modeling.
Topics: Bioprinting; Drug Evaluation, Preclinical; Endothelial Cells; Humans; Hydrogels; Microfibrils; Myocardium; Myocytes, Cardiac; Organoids; Printing, Three-Dimensional; Regenerative Medicine; Tissue Engineering; Tissue Scaffolds
PubMed: 27710832
DOI: 10.1016/j.biomaterials.2016.09.003 -
Progress in Retinal and Eye Research May 2021The Zonule of Zinn, or ciliary zonule, is the elaborate system of extracellular fibers that centers the lens in the eye. In humans, the fibers transmit forces that... (Review)
Review
The Zonule of Zinn, or ciliary zonule, is the elaborate system of extracellular fibers that centers the lens in the eye. In humans, the fibers transmit forces that flatten the lens during the process of disaccommodation, thereby bringing distant objects into focus. Zonular fibers are composed almost entirely of 10-12 nm-wide microfibrils, of which polymerized fibrillin is the most abundant component. The thickest fibers have a fascicular organization, where hundreds or thousands of microfibrils are gathered into micrometer-wide bundles. Many such bundles are aggregated to form a fiber. Dozens of proteins comprise the zonule. Most are derived from cells of the non-pigmented ciliary epithelium in the pars plana region, although some are probably contributed by the lens and perhaps other tissues of the anterior segment. Zonular fibers are viscoelastic cables but their component microfibrils are rather stiff structures. Thus, the elastic properties of the fibers likely stem from lateral interactions between microfibrils. Rupture of zonular fibers and subsequent lens dislocation (ectopia lentis) can result from blunt force trauma or be a sequela of other eye diseases, notably exfoliation syndrome. Ectopia lentis is also a feature of syndromic conditions caused typically by mutations in microfibril-associated genes. The resulting ocular phenotypes raise the possibility that the zonule regulates lens size and shape, globe size, and even corneal topology, in addition to its well-recognized role in accommodation.
Topics: Ciliary Body; Ectopia Lentis; Fibrillins; Humans; Lens, Crystalline; Microfibrils
PubMed: 32980533
DOI: 10.1016/j.preteyeres.2020.100902 -
Experimental Eye Research Mar 2015Elastic tissue was first described well over a hundred years ago and has since been identified in nearly every part of the body. In this review, we examine elastic... (Review)
Review
Elastic tissue was first described well over a hundred years ago and has since been identified in nearly every part of the body. In this review, we examine elastic tissue in the corneal stroma with some mention of other ocular structures which have been more thoroughly described in the past. True elastic fibers consist of an elastin core surrounded by fibrillin microfibrils. However, the presence of elastin fibers is not a requirement and some elastic tissue is comprised of non-elastin-containing bundles of microfibrils. Fibers containing a higher relative amount of elastin are associated with greater elasticity and those without elastin, with structural support. Recently it has been shown that the microfibrils, not only serve mechanical roles, but are also involved in cell signaling through force transduction and the release of TGF-β. A well characterized example of elastin-free microfibril bundles (EFMBs) is found in the ciliary zonules which suspend the crystalline lens in the eye. Through contraction of the ciliary muscle they exert enough force to reshape the lens and thereby change its focal point. It is believed that the molecules comprising these fibers do not turn-over and yet retain their tensile strength for the life of the animal. The mechanical properties of the cornea (strength, elasticity, resiliency) would suggest that EFMBs are present there as well. However, many authors have reported that, although present during embryonic and early postnatal development, EFMBs are generally not present in adults. Serial-block-face imaging with a scanning electron microscope enabled 3D reconstruction of elements in murine corneas. Among these elements were found fibers that formed an extensive network throughout the cornea. In single sections these fibers appeared as electron dense patches. Transmission electron microscopy provided additional detail of these patches and showed them to be composed of fibrils (∼10 nm diameter). Immunogold evidence clearly identified these fibrils as fibrillin EFMBs and EFMBs were also observed with TEM (without immunogold) in adult mammals of several species. Evidence of the presence of EFMBs in adult corneas will hopefully pique an interest in further studies that will ultimately improve our understanding of the cornea's biomechanical properties and its capacity to repair.
Topics: Animals; Corneal Stroma; Elastin; Fibrillins; Humans; Imaging, Three-Dimensional; Immunohistochemistry; Microfibrils; Microfilament Proteins; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission
PubMed: 25613072
DOI: 10.1016/j.exer.2015.01.014 -
Ageing Research Reviews Mar 2021Elastic fibers are essential constituents of the extracellular matrix of higher vertebrates and endow several tissues and organs including lungs, skin and blood vessels... (Review)
Review
Elastic fibers are essential constituents of the extracellular matrix of higher vertebrates and endow several tissues and organs including lungs, skin and blood vessels with elasticity and resilience. During the human lifespan, elastic fibers are exposed to a variety of enzymatic, chemical and biophysical influences, and accumulate damage due to their low turnover. Aging of elastin and elastic fibers involves enzymatic degradation, oxidative damage, glycation, calcification, aspartic acid racemization, binding of lipids and lipid peroxidation products, carbamylation and mechanical fatigue. These processes can trigger an impairment or loss of elastic fiber function and are associated with severe pathologies. There are different inherited or acquired pathological conditions, which influence the structure and function of elastic fibers and microfibrils predominantly in the cardiorespiratory system and skin. Inherited elastic-fiber pathologies have a direct or indirect impact on elastic-fiber formation due to mutations in the fibrillin genes (fibrillinopathies), in the elastin gene (elastinopathies) or in genes encoding proteins that are associated with microfibrils or elastic fibers. Acquired elastic-fiber pathologies appear age-related or as a result of multiple factors impairing tissue homeostasis. This review gives an overview on the fate of elastic fibers over the human lifespan in health and disease.
Topics: Aging; Animals; Elastic Tissue; Elastin; Fibrillins; Humans; Microfilament Proteins
PubMed: 33434682
DOI: 10.1016/j.arr.2021.101255 -
Molecular Plant Jan 2023All plant cells are surrounded by a cell wall that provides cohesion, protection, and a means of directional growth to plants. Cellulose microfibrils contribute the main... (Review)
Review
All plant cells are surrounded by a cell wall that provides cohesion, protection, and a means of directional growth to plants. Cellulose microfibrils contribute the main biomechanical scaffold for most of these walls. The biosynthesis of cellulose, which typically is the most prominent constituent of the cell wall and therefore Earth's most abundant biopolymer, is finely attuned to developmental and environmental cues. Our understanding of the machinery that catalyzes and regulates cellulose biosynthesis has substantially improved due to recent technological advances in, for example, structural biology and microscopy. Here, we provide a comprehensive overview of the structure, function, and regulation of the cellulose synthesis machinery and its regulatory interactors. We aim to highlight important knowledge gaps in the field, and outline emerging approaches that promise a means to close those gaps.
Topics: Embryophyta; Cellulose; Plants; Cell Wall; Glucosyltransferases
PubMed: 36564945
DOI: 10.1016/j.molp.2022.12.015 -
Frontiers in Physiology 2016A characteristic feature of liver cirrhosis is the accumulation of large amounts of connective tissue with the prevailing content of type I collagen. Elastin is a minor... (Review)
Review
A characteristic feature of liver cirrhosis is the accumulation of large amounts of connective tissue with the prevailing content of type I collagen. Elastin is a minor connective tissue component in normal liver but it is actively synthesized by hepatic stellate cells and portal fibroblasts in diseased liver. The accumulation of elastic fibers in later stages of liver fibrosis may contribute to the decreasing reversibility of the disease with advancing time. Elastin is formed by polymerization of tropoelastin monomers. It is an amorphous protein highly resistant to the action of proteases that forms the core of elastic fibers. Microfibrils surrounding the core are composed of fibrillins that bind a number of proteins involved in fiber formation. They include microfibril-associated glycoproteins (MAGPs), microfibrillar-associated proteins (MFAPs) and fibulins. Lysyl oxidase (LOX) and lysyl oxidase-like proteins (LOXLs) are responsible for tropoelastin cross-linking and polymerization. TGF-β complexes attached to microfibrils release this cytokine and influence the behavior of the cells in the neighborhood. The role of TGF-β as the main profibrotic cytokine in the liver is well-known and the release of the cytokines of TGF-β superfamily from their storage in elastic fibers may affect the course of fibrosis. Elastic fibers are often studied in the tissues where they provide elasticity and resilience but their role is no longer viewed as purely mechanical. Tropoelastin, elastin polymer and elastin peptides resulting from partial elastin degradation influence fibroblastic and inflammatory cells as well as angiogenesis. A similar role may be performed by elastin in the liver. This article reviews the results of the research of liver elastic fibers on the background of the present knowledge of elastin biochemistry and physiology. The regulation of liver elastin synthesis and degradation may be important for the outcome of liver fibrosis.
PubMed: 27826254
DOI: 10.3389/fphys.2016.00491 -
Proceedings of the National Academy of... Jun 2023Fibrillin-1 is an extracellular matrix protein that assembles into microfibrils which provide critical functions in large blood vessels and other tissues. Mutations in...
Fibrillin-1 is an extracellular matrix protein that assembles into microfibrils which provide critical functions in large blood vessels and other tissues. Mutations in the fibrillin-1 gene are associated with cardiovascular, ocular, and skeletal abnormalities in Marfan syndrome. Here, we reveal that fibrillin-1 is critical for angiogenesis which is compromised by a typical Marfan mutation. In the mouse retina vascularization model, fibrillin-1 is present in the extracellular matrix at the angiogenic front where it colocalizes with microfibril-associated glycoprotein-1, MAGP1. In mice, a model of Marfan syndrome, MAGP1 deposition is reduced, endothelial sprouting is decreased, and tip cell identity is impaired. Cell culture experiments confirmed that fibrillin-1 deficiency alters vascular endothelial growth factor-A/Notch and Smad signaling which regulate the acquisition of endothelial tip cell/stalk cell phenotypes, and we showed that modulation of MAGP1 expression impacts these pathways. Supplying the growing vasculature of mice with a recombinant C-terminal fragment of fibrillin-1 corrects all defects. Mass spectrometry analyses showed that the fibrillin-1 fragment alters the expression of various proteins including ADAMTS1, a tip cell metalloprotease and matrix-modifying enzyme. Our data establish that fibrillin-1 is a dynamic signaling platform in the regulation of cell specification and matrix remodeling at the angiogenic front and that mutant fibrillin-1-induced defects can be rescued pharmacologically using a C-terminal fragment of the protein. These findings, identify fibrillin-1, MAGP1, and ADAMTS1 in the regulation of endothelial sprouting, and contribute to our understanding of how angiogenesis is regulated. This knowledge may have critical implications for people with Marfan syndrome.
Topics: Animals; Mice; Extracellular Matrix; Fibrillin-1; Marfan Syndrome; Vascular Endothelial Growth Factor A
PubMed: 37252964
DOI: 10.1073/pnas.2221742120