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The FEBS Journal Dec 2015Basement membranes (BMs) are thin sheets of extracellular matrix that outline epithelia, muscle fibers, blood vessels and peripheral nerves. The current view of BM... (Review)
Review
Basement membranes (BMs) are thin sheets of extracellular matrix that outline epithelia, muscle fibers, blood vessels and peripheral nerves. The current view of BM structure and functions is based mainly on transmission electron microscopy imaging, in vitro protein binding assays, and phenotype analysis of human patients, mutant mice and invertebrata. Recently, MS-based protein analysis, biomechanical testing and cell adhesion assays with in vivo derived BMs have led to new and unexpected insights. Proteomic analysis combined with ultrastructural studies showed that many BMs undergo compositional and structural changes with advancing age. Atomic force microscopy measurements in combination with phenotype analysis have revealed an altered mechanical stiffness that correlates with specific BM pathologies in mutant mice and human patients. Atomic force microscopy-based height measurements strongly suggest that BMs are more than two-fold thicker than previously estimated, providing greater freedom for modelling the large protein polymers within BMs. In addition, data gathered using BMs extracted from mutant mice showed that laminin has a crucial role in BM stability. Finally, recent evidence demonstrate that BMs are bi-functionally organized, leading to the proposition that BM-sidedness contributes to the alternating epithelial and stromal tissue arrangements that are found in all metazoan species. We propose that BMs are ancient structures with tissue-organizing functions and were essential in the evolution of metazoan species.
Topics: Animals; Basement Membrane; Humans; Microscopy, Atomic Force; Proteomics
PubMed: 26299746
DOI: 10.1111/febs.13495 -
Biochemical Society Transactions Dec 2022Basement membranes (BMs) are structured regions of the extracellular matrix that provide multiple functions including physical support and acting as a barrier, as a...
Basement membranes (BMs) are structured regions of the extracellular matrix that provide multiple functions including physical support and acting as a barrier, as a repository for nutrients and growth factors, and as biophysical signalling hubs. At the core of all BMs is the laminin (LM) family of proteins. These large heterotrimeric glycoproteins are essential for tissue integrity, and differences between LM family members represent a key nexus in dictating context and tissue-specific functions. These variations reflect genetic diversity within the family, which allows for multiple structurally and functionally distinct heterotrimers to be produced, each with different architectures and affinities for other matrix proteins and cell surface receptors. The ratios of these LM isoforms also influence the biophysical properties of a BM owing to differences in their relative ability to form polymers or networks. Intriguingly, the LM superfamily is further diversified through the related netrin family of proteins and through alternative splicing leading to the generation of non-LM short proteins known as the laminin N-terminus (LaNt) domain proteins. Both the netrins and LaNt proteins contain structural domains involved in LM-to-LM interaction and network assembly. Emerging findings indicate that one netrin and at least one LaNt protein can potently influence the structure and function of BMs, disrupting the networks, changing physical properties, and thereby influencing tissue function. These findings are altering the way that we think about LM polymerisation and, in the case of the LaNt proteins, suggest a hitherto unappreciated form of LM self-regulation.
Topics: Laminin; Basement Membrane; Protein Isoforms; Alternative Splicing; Extracellular Matrix
PubMed: 36355367
DOI: 10.1042/BST20210240 -
Cellular and Molecular Life Sciences :... Feb 2022In the cornea, the epithelial basement membrane (EBM) and corneal endothelial Descemet's basement membrane (DBM) critically regulate the localization, availability and,... (Review)
Review
In the cornea, the epithelial basement membrane (EBM) and corneal endothelial Descemet's basement membrane (DBM) critically regulate the localization, availability and, therefore, the functions of transforming growth factor (TGF)β1, TGFβ2, and platelet-derived growth factors (PDGF) that modulate myofibroblast development. Defective regeneration of the EBM, and notably diminished perlecan incorporation, occurs via several mechanisms and results in excessive and prolonged penetration of pro-fibrotic growth factors into the stroma. These growth factors drive mature myofibroblast development from both corneal fibroblasts and bone marrow-derived fibrocytes, and then the persistence of these myofibroblasts and the disordered collagens and other matrix materials they produce to generate stromal scarring fibrosis. Corneal stromal fibrosis often resolves completely if the inciting factor is removed and the BM regenerates. Similar defects in BM regeneration are likely associated with the development of fibrosis in other organs where perlecan has a critical role in the modulation of signaling by TGFβ1 and TGFβ2. Other BM components, such as collagen type IV and collagen type XIII, are also critical regulators of TGF beta (and other growth factors) in the cornea and other organs. After injury, BM components are dynamically secreted and assembled through the cooperation of neighboring cells-for example, the epithelial cells and keratocytes for the corneal EBM and corneal endothelial cells and keratocytes for the corneal DBM. One of the most critical functions of these reassembled BMs in all organs is to modulate the pro-fibrotic effects of TGFβs, PDGFs and other growth factors between tissues that comprise the organ.
Topics: Animals; Basement Membrane; Corneal Diseases; Fibrosis; Heparan Sulfate Proteoglycans; Humans; Transforming Growth Factor beta
PubMed: 35188596
DOI: 10.1007/s00018-022-04184-7 -
Experimental Animals Aug 2022Tensin 2 (TNS2), a focal adhesion protein, is considered to anchor focal adhesion proteins to β integrin as an integrin adaptor protein and/or serve as a scaffold to... (Review)
Review
Tensin 2 (TNS2), a focal adhesion protein, is considered to anchor focal adhesion proteins to β integrin as an integrin adaptor protein and/or serve as a scaffold to facilitate the interactions of these proteins. In the kidney, TNS2 localizes to the basolateral surface of glomerular epithelial cells, i.e., podocytes. Loss of TNS2 leads to the development of glomerular basement membrane lesions and abnormal accumulation of extracellular matrix in maturing glomeruli during the early postnatal stages. It subsequently results in podocyte foot process effacement, eventually leading to glomerulosclerosis. Histopathological features of the affected glomeruli in the middle stage of the disease include expansion of the mesangial matrix without mesangial cell proliferation. In this review, we provide an overview of TNS2-deficient nephropathy and discuss the potential mechanism underlying this mechanosensitive nephropathy, which may be applicable to other glomerulonephropathies, such as CD151-deficient nephropathy and Alport syndrome. The onset of TNS2-deficient nephropathy strictly depends on the genetic background, indicating the presence of critical modifier genes. A better understanding of molecular mechanisms of mechanosensitive nephropathy may open new avenues for the management of patients with glomerulonephropathies.
Topics: Animals; Genetic Predisposition to Disease; Glomerular Basement Membrane; Humans; Kidney; Kidney Diseases; Podocytes
PubMed: 35444113
DOI: 10.1538/expanim.22-0031 -
Matrix Biology : Journal of the... Jan 2017Naturally-derived materials have been extensively used as 3D cellular matrices as their inherent bioactivity makes them suitable for the study of many cellular... (Review)
Review
Naturally-derived materials have been extensively used as 3D cellular matrices as their inherent bioactivity makes them suitable for the study of many cellular processes. Nevertheless, lot-to-lot variability, inability to decouple biochemical and biophysical properties and, in some types, their tumor-derived nature limits their translational potential and reliability. One innovative approach to overcome these limitations has focused on incorporating bioactivity into cytocompatible, synthetic hydrogels that present tunable physicochemical properties. This review provides an overview of successful approaches to convey basement membrane-like bioactivity into 3D artificial hydrogel matrices in order to recapitulate cellular responses to native matrices. Recent advances involving biofunctionalization of synthetic hydrogels via incorporation of bioactive motifs that promote cell-matrix interactions and cell-directed matrix degradation will be discussed. This review highlights how the tunable physicochemical properties of biofunctionalized synthetic hydrogel matrices can be exploited to study the separate contributions of biochemical and biophysical matrix properties to different cellular processes.
Topics: Basement Membrane; Biomimetic Materials; Cell Communication; Cell Line, Tumor; Collagen; Collagen Type IV; Drug Combinations; Epithelial Cells; Extracellular Matrix; Heparan Sulfate Proteoglycans; Humans; Hydrogels; Integrins; Laminin; Membrane Glycoproteins; Proteoglycans; Receptors, Cell Surface; Signal Transduction
PubMed: 27283894
DOI: 10.1016/j.matbio.2016.06.002 -
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 -
Developmental Cell Nov 2017Cell invasion across basement membrane barriers is important in both normal development and cancer metastasis. In this issue of Developmental Cell, Naegeli et al.... (Review)
Review
Cell invasion across basement membrane barriers is important in both normal development and cancer metastasis. In this issue of Developmental Cell, Naegeli et al. (2017) identify a mechanism for breaching basement membranes. Localized lysosome exocytosis fuels generation of large, invasive cellular protrusions that expand tiny basement membrane openings.
Topics: Actins; Animals; Basement Membrane; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cell Movement; Exocytosis; Humans; Lysosomes
PubMed: 29161585
DOI: 10.1016/j.devcel.2017.11.005 -
Journal of Cell Science May 2015Basement membranes are a dense, sheet-like form of extracellular matrix (ECM) that underlie epithelia and endothelia, and surround muscle, fat and Schwann cells.... (Review)
Review
Basement membranes are a dense, sheet-like form of extracellular matrix (ECM) that underlie epithelia and endothelia, and surround muscle, fat and Schwann cells. Basement membranes separate tissues and protect them from mechanical stress. Although traditionally thought of as a static support structure, a growing body of evidence suggests that dynamic basement membrane deposition and modification instructs coordinated cellular behaviors and acts mechanically to sculpt tissues. In this Commentary, we highlight recent studies that support the idea that far from being a passive matrix, basement membranes play formative roles in shaping tissues.
Topics: Animals; Basement Membrane; Cell Polarity; Collagen; Humans; Models, Biological; Organ Specificity
PubMed: 25717004
DOI: 10.1242/jcs.168021 -
Biomacromolecules Aug 2022Advancements in the field of tissue engineering have led to the elucidation of physical and chemical characteristics of physiological basement membranes (BM) as... (Review)
Review
Advancements in the field of tissue engineering have led to the elucidation of physical and chemical characteristics of physiological basement membranes (BM) as specialized forms of the extracellular matrix. Efforts to recapitulate the intricate structure and biological composition of the BM have encountered various advancements due to its impact on cell fate, function, and regulation. More attention has been paid to synthesizing biocompatible and biofunctional fibrillar scaffolds that closely mimic the natural BM. Specific modifications in biomimetic BM have paved the way for the development of models like alveolar-capillary barrier, airway models, skin, blood-brain barrier, kidney barrier, and metastatic models, which can be used for personalized drug screening, understanding physiological and pathological pathways, and tissue implants. In this Review, we focus on the structure, composition, and functions of BM and the ongoing efforts to mimic it synthetically. Light has been shed on the advantages and limitations of various forms of biomimetic BM scaffolds including porous polymeric membranes, hydrogels, and electrospun membranes This Review further elaborates and justifies the significance of BM mimics in tissue engineering, in particular in the development of organ model systems.
Topics: Basement Membrane; Cell Differentiation; Extracellular Matrix; Skin; Tissue Engineering; Tissue Scaffolds
PubMed: 35839343
DOI: 10.1021/acs.biomac.2c00402 -
Developmental Biology Nov 2017Collagen IV networks endow basement membranes (BMs) with remarkable tensile strength and function as morphoregulatory substrata for diverse tissue-specific developmental... (Review)
Review
Collagen IV networks endow basement membranes (BMs) with remarkable tensile strength and function as morphoregulatory substrata for diverse tissue-specific developmental events. A complex repertoire of intracellular and extracellular molecular interactions are required for collagen IV secretion and supramolecular assembly into BMs. These include intracellular chaperones such as Heat shock protein 47 (Hsp47) and the chaperone-binding trafficking protein Transport and Golgi organization protein 1 (Tango1). Mutations in these proteins lead to compromised collagen IV protomer stability and secretion, leading to defective BM assembly and function. In addition to intracellular chaperones, a role for extracellular chaperones orchestrating the transport, supramolecular assembly, and architecture of collagen IV in BM is emerging. We present evidence derived from evolutionarily distant model organisms that supports an extracellular collagen IV chaperone-like activity for the matricellular protein SPARC (Secreted Protein, Acidic, Rich in Cysteine). Loss of SPARC disrupts BM homeostasis and compromises tissue biomechanics and physiological function. Thus, the combined contributions of intracellular and extracellular collagen IV-associated chaperones and chaperone-like proteins are critical to ensure proper secretion and stereotypic assembly of collagen IV networks in BMs.
Topics: Animals; Basement Membrane; Collagen Type IV; Evolution, Molecular; Humans; Osteonectin; Protein Folding; Protein Transport
PubMed: 28982537
DOI: 10.1016/j.ydbio.2017.09.037