The Experts below are selected from a list of 7161 Experts worldwide ranked by ideXlab platform
Paolo Bonaldo - One of the best experts on this subject based on the ideXlab platform.
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Collagen VI in healthy and diseased nervous system
Disease models & mechanisms, 2018Co-Authors: Ilaria Gregorio, Paolo Bonaldo, Paola Braghetta, Matilde CesconAbstract:Collagen VI is a major extracellular matrix protein exerting a number of functions in different tissues, spanning from biomechanical to regulatory signals in the cell surVIval processes, and playing key roles in maintaining the stemness or determining the differentiation of several types of cells. In the last couple of years, emerging findings on Collagen VI have led to increased interest in its role in the nervous system. The role of this protein in the peripheral nervous system was intensely studied and characterized in detail. Collagen VI acts as a regulator of Schwann cell differentiation and is required for preserVIng peripheral nerve myelination, function and structure, as well as for orchestrating nerve regeneration after injury. Although the role and distribution of Collagen VI in the peripheral nervous system is now well established, the role of this distinctive extracellular matrix component in the central nervous system, along with its links to human neurological and neurodegenerative disorders, remains an open field of investigation. In this ReVIew, we summarize and discuss a number of recent findings related to Collagen VI in the central and peripheral nervous systems. We further link these findings to different aspects of the protein that are relevant to human diseases in these compartments in order to proVIde a comprehensive overVIew of the roles of this key matrix component in the nervous system.
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CMG2/ANTXR2 regulates extracellular Collagen VI which accumulates in hyaline fibromatosis syndrome.
Nature communications, 2017Co-Authors: Jérôme Bürgi, Béatrice Kunz, Laurence Abrami, Julie Deuquet, Alessandra Piersigilli, Sabine Scholl-bürgi, Ekkehart Lausch, Sheila Unger, Andrea Superti-furga, Paolo BonaldoAbstract:Loss-of-function mutations in capillary morphogenesis gene 2 (CMG2/ANTXR2), a transmembrane surface protein, cause hyaline fibromatosis syndrome (HFS), a severe genetic disorder that is characterized by large subcutaneous nodules, gingival hypertrophy and severe painful joint contracture. Here we show that CMG2 is an important regulator of Collagen VI homoeostasis. CMG2 loss of function promotes accumulation of Collagen VI in patients, leading in particular to nodule formation. Similarly, Collagen VI accumulates massively in uteri of Antxr2−/− mice, which do not display changes in Collagen gene expression, and leads to progressive fibrosis and sterility. Crossing Antxr2−/− with Col6a1−/− mice leads to restoration of uterine structure and reversion of female infertility. We also demonstrate that CMG2 may act as a signalling receptor for Collagen VI and mediates its intracellular degradation. Hyaline fibromatosis syndrome (HFS) is a hereditary disease characterized by nodular cutaneous lesions and joint pain. Here Burgiet al. show that CMG2/ANTXR2 regulates Collagen VI abundance, with loss-of-function mutations promoting Collagen VI accumulation in HFS nodules and myometrial Collagen deposition and sterility in mice, which can be rescued by depleting Collagen VI.
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Col6a1 Null Mice as a Model to Study Skin Phenotypes in Patients with Collagen VI Related Myopathies: Expression of Classical and Novel Collagen VI Variants during Wound Healing
2016Co-Authors: Ra Lettmann, Paolo Bonaldo, Wilhelm Bloch, Tobias Maaß, Anja Niehoff, Jan-niklas Schulz, Beate Eckes, Sabine A. Eming, Mats Paulsson, Raimund WagenerAbstract:Patients suffering from Collagen VI related myopathies caused by mutations in COL6A1, COL6A2 and COL6A3 often also display skin abnormalities, like formation of keloids or ‘‘cigarette paper’ ’ scars, dry skin, striae rubrae and keratosis pilaris (follicular keratosis). Here we evaluated if Col6a1 null mice, an established animal model for the muscle changes in Collagen VI related myopathies, are also suitable for the study of mechanisms leading to the skin pathology. We performed a comprehensive study of the expression of all six Collagen VI chains in unwounded and challenged skin of wild type and Col6a1 null mice. Expression of Collagen VI chains is regulated in both skin wounds and bleomycin-induced fibrosis and the Collagen VI a3 chain is proteolytically processed in both wild type and Col6a1 null mice. Interestingly, we detected a decreased tensile strength of the skin and an altered Collagen fibril and basement membrane architecture in Col6a1 null mice, the latter being features that are also found in Collagen VI myopathy patients. Although Col6a1 null mice do not display an overt wound healing defect, these mice are a relevant animal model to study the skin pathology in Collagen V
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Lack of Collagen VI promotes neurodegeneration by impairing autophagy and inducing apoptosis during aging.
Aging, 2016Co-Authors: Matilde Cescon, Peiwen Chen, Ilaria Gregorio, Silvia Castagnaro, Paolo BonaldoAbstract:Collagen VI is an extracellular matrix (ECM) protein with a broad distribution in different tissues and mostly deposited at the close periphery of the cell surface. PreVIous studies revealed that Collagen VI protects neurons from the toxicity of amyloid-βpeptides and from UV-induced damage. However, the physiological role of this protein in the central nervous system (CNS) remains unknown. Here, we established primary neural cultures from murine cortex and hippocampus, and carried out in VItro and in VIvo studies in wild-type and Collagen VI null (Col6a1-/-) mice. Col6a1-/- neural cultures displayed an increased incidence of spontaneous apoptosis and higher vulnerability to oxidative stress, accompanied by altered regulation of autophagy with increased p62 protein levels and decreased LC3 lipidation. Analysis of brain sections confirmed increased apoptosis and abnormal regulation of autophagy in the CNS of Collagen VI-deficient animals. To investigate the in VIvo physiological consequences of these CNS defects, we carried out functional studies and found that motor and memory task performances were impaired in aged Col6a1-/-mice. These findings indicate that lack of Collagen VI leads to spontaneous apoptosis and defective autophagy in neural cells, and point at a protective role for this ECM protein in the CNS during physiological aging.
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heterogeneity of Collagen VI microfibrils structural analysis of non Collagenous regions
Journal of Biological Chemistry, 2016Co-Authors: Tobias Maas, Clair Baldock, Paolo Bonaldo, Sandra Lettmann, Mats Paulsson, Matthias Mörgelin, Christopher P Bayley, Raimund WagenerAbstract:Collagen VI, a Collagen with uncharacteristically large N- and C-terminal non-Collagenous regions, forms a distinct microfibrillar network in most connective tissues. It was long considered to consist of three genetically distinct α chains (α1, α2, and α3). Intracellularly, heterotrimeric molecules associate to form dimers and tetramers, which are then secreted and assembled to microfibrils. The identification of three novel long Collagen VI α chains, α4, α5, and α6, led to the question if and how these may substitute for the long α3 chain in Collagen VI assembly. Here, we studied structural features of the novel long chains and analyzed the assembly of these into tetramers and microfibrils. N- and C-terminal globular regions of Collagen VI were recombinantly expressed and studied by small angle x-ray scattering (SAXS). Ab initio models of the N-terminal globular regions of the α4, α5, and α6 chains showed a C-shaped structure similar to that found for the α3 chain. Single particle EM nanostructure of the N-terminal globular region of the α4 chain confirmed the C-shaped structure revealed by SAXS. Immuno-EM of Collagen VI extracted from tissue revealed that like the α3 chain the novel long chains assemble to homotetramers that are incorporated into mixed microfibrils. Moreover, SAXS models of the C-terminal globular regions of the α1, α2, α4, and α6 chains were generated. Interestingly, the α1, α2, and α4 C-terminal globular regions dimerize. These self-interactions may play a role in tetramer formation.
Raimund Wagener - One of the best experts on this subject based on the ideXlab platform.
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Collagen VI Contains Multiple Host Defense Peptides with Potent In VIvo ActiVIty.
Journal of immunology (Baltimore Md. : 1950), 2018Co-Authors: Suado M Abdillahi, Tobias Maaß, Raimund Wagener, Gopinath Kasetty, Adam A. Strömstedt, Maria Baumgarten, Ramesh Tati, Sara L. Nordin, Björn Walse, Artur SchmidtchenAbstract:Collagen VI is a ubiquitous extracellular matrix component that forms extensive microfibrillar networks in most connective tissues. In this study, we describe for the first time, to our knowledge, that the Collagen VI von Willebrand factor type A-like domains exhibit a broad-spectrum antimicrobial actiVIty against Gram-positive and Gram-negative bacteria in human skin infections in VIvo. In silico sequence and structural analysis of VWA domains revealed that they contain cationic and amphipathic peptide sequence motifs, which might explain the antimicrobial nature of Collagen VI. In VItro and in VIvo studies show that these peptides exhibited significant antibacterial actiVIty against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa through membrane disruption. Our findings shed new light on the role of Collagen VI-derived peptides in innate host defense and proVIde templates for development of peptide-based antibacterial therapies.
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Col6a1 Null Mice as a Model to Study Skin Phenotypes in Patients with Collagen VI Related Myopathies: Expression of Classical and Novel Collagen VI Variants during Wound Healing
2016Co-Authors: Ra Lettmann, Paolo Bonaldo, Wilhelm Bloch, Tobias Maaß, Anja Niehoff, Jan-niklas Schulz, Beate Eckes, Sabine A. Eming, Mats Paulsson, Raimund WagenerAbstract:Patients suffering from Collagen VI related myopathies caused by mutations in COL6A1, COL6A2 and COL6A3 often also display skin abnormalities, like formation of keloids or ‘‘cigarette paper’ ’ scars, dry skin, striae rubrae and keratosis pilaris (follicular keratosis). Here we evaluated if Col6a1 null mice, an established animal model for the muscle changes in Collagen VI related myopathies, are also suitable for the study of mechanisms leading to the skin pathology. We performed a comprehensive study of the expression of all six Collagen VI chains in unwounded and challenged skin of wild type and Col6a1 null mice. Expression of Collagen VI chains is regulated in both skin wounds and bleomycin-induced fibrosis and the Collagen VI a3 chain is proteolytically processed in both wild type and Col6a1 null mice. Interestingly, we detected a decreased tensile strength of the skin and an altered Collagen fibril and basement membrane architecture in Col6a1 null mice, the latter being features that are also found in Collagen VI myopathy patients. Although Col6a1 null mice do not display an overt wound healing defect, these mice are a relevant animal model to study the skin pathology in Collagen V
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heterogeneity of Collagen VI microfibrils structural analysis of non Collagenous regions
Journal of Biological Chemistry, 2016Co-Authors: Tobias Maas, Clair Baldock, Paolo Bonaldo, Sandra Lettmann, Mats Paulsson, Matthias Mörgelin, Christopher P Bayley, Raimund WagenerAbstract:Collagen VI, a Collagen with uncharacteristically large N- and C-terminal non-Collagenous regions, forms a distinct microfibrillar network in most connective tissues. It was long considered to consist of three genetically distinct α chains (α1, α2, and α3). Intracellularly, heterotrimeric molecules associate to form dimers and tetramers, which are then secreted and assembled to microfibrils. The identification of three novel long Collagen VI α chains, α4, α5, and α6, led to the question if and how these may substitute for the long α3 chain in Collagen VI assembly. Here, we studied structural features of the novel long chains and analyzed the assembly of these into tetramers and microfibrils. N- and C-terminal globular regions of Collagen VI were recombinantly expressed and studied by small angle x-ray scattering (SAXS). Ab initio models of the N-terminal globular regions of the α4, α5, and α6 chains showed a C-shaped structure similar to that found for the α3 chain. Single particle EM nanostructure of the N-terminal globular region of the α4 chain confirmed the C-shaped structure revealed by SAXS. Immuno-EM of Collagen VI extracted from tissue revealed that like the α3 chain the novel long chains assemble to homotetramers that are incorporated into mixed microfibrils. Moreover, SAXS models of the C-terminal globular regions of the α1, α2, α4, and α6 chains were generated. Interestingly, the α1, α2, and α4 C-terminal globular regions dimerize. These self-interactions may play a role in tetramer formation.
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Collagen VI–NG2 axis in human tendon fibroblasts under conditions mimicking injury response
Matrix biology : journal of the International Society for Matrix Biology, 2016Co-Authors: Francesca Sardone, Luciano Merlini, Raimund Wagener, Matilde Cescon, Francesca Tagliavini, Stefano Squarzoni, Spartaco Santi, Francesco Traina, Nadir M. Maraldi, Paolo BonaldoAbstract:In response to injury, tendon fibroblasts are activated, migrate to the wound, and contribute to tissue repair by producing and organizing the extracellular matrix. Collagen VI is a microfibrillar Collagen enriched in the pericellular matrix of tendon fibroblasts with a potential regulatory role in tendon repair mechanism. We investigated the molecular basis of the interaction between Collagen VI and the cell membrane both in tissue sections and fibroblast cultures of human tendon, and analyzed the deposition of Collagen VI during migration and myofibroblast trans-differentiation, two crucial events for tendon repair. Tendon fibroblast displayed a Collagen VI microfibrillar network closely associated with the cell surface. Binding of Collagen VI with the cell membrane was mediated by NG2 proteoglycan, as demonstrated by in VItro perturbation of Collagen VI–NG2 interaction with a NG2-blocking antibody. Cultures subjected to wound healing scratch assay displayed Collagen VI–NG2 complexes at the trailing edge of migrating cells, suggesting a potential role in cell migration. In fact, the addition of a NG2-blocking antibody led to an impairment of cell polarization and delay of wound closure. Similar results were obtained after in VItro perturbation of Collagen VI extracellular assembly with the 3C4 anti-Collagen VI antibody and in Collagen VI-deficient tendon cultures of a Ullrich congenital muscular dystrophy patient carrying mutations in COL6A2 gene. Moreover, in VItro treatment with transforming growth factor β1 (TGFβ1) induced a dramatic reduction of NG2 expression, both at protein and mRNA transcript level, and the impairment of Collagen VI association with the cell membrane. Instead, Collagen VI was still detectable in the extracellular matrix in association with ED-A fibronectin and Collagen I, which were strongly induced by TGFβ1 treatment. Our findings reveal a critical role of the NG2 proteoglycan for the binding of Collagen VI to the surface of tendon fibroblasts. By interacting with NG2 proteoglycan and other extracellular matrix proteins, Collagen VI regulates fibroblasts behaVIor and the assembly of tendon matrix, thereby playing a crucial role in tendon repair.
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Heterogeneity of Collagen VI Microfibrils: STRUCTURAL ANALYSIS OF NON-CollagenOUS REGIONS.
The Journal of biological chemistry, 2016Co-Authors: Tobias Maaß, Clair Baldock, Paolo Bonaldo, Sandra Lettmann, Mats Paulsson, Matthias Mörgelin, Christopher P Bayley, Raimund WagenerAbstract:Collagen VI, a Collagen with uncharacteristically large N- and C-terminal non-Collagenous regions, forms a distinct microfibrillar network in most connective tissues. It was long considered to consist of three genetically distinct α chains (α1, α2, and α3). Intracellularly, heterotrimeric molecules associate to form dimers and tetramers, which are then secreted and assembled to microfibrils. The identification of three novel long Collagen VI α chains, α4, α5, and α6, led to the question if and how these may substitute for the long α3 chain in Collagen VI assembly. Here, we studied structural features of the novel long chains and analyzed the assembly of these into tetramers and microfibrils. N- and C-terminal globular regions of Collagen VI were recombinantly expressed and studied by small angle x-ray scattering (SAXS). Ab initio models of the N-terminal globular regions of the α4, α5, and α6 chains showed a C-shaped structure similar to that found for the α3 chain. Single particle EM nanostructure of the N-terminal globular region of the α4 chain confirmed the C-shaped structure revealed by SAXS. Immuno-EM of Collagen VI extracted from tissue revealed that like the α3 chain the novel long chains assemble to homotetramers that are incorporated into mixed microfibrils. Moreover, SAXS models of the C-terminal globular regions of the α1, α2, α4, and α6 chains were generated. Interestingly, the α1, α2, and α4 C-terminal globular regions dimerize. These self-interactions may play a role in tetramer formation.
Peiwen Chen - One of the best experts on this subject based on the ideXlab platform.
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Lack of Collagen VI promotes neurodegeneration by impairing autophagy and inducing apoptosis during aging.
Aging, 2016Co-Authors: Matilde Cescon, Peiwen Chen, Ilaria Gregorio, Silvia Castagnaro, Paolo BonaldoAbstract:Collagen VI is an extracellular matrix (ECM) protein with a broad distribution in different tissues and mostly deposited at the close periphery of the cell surface. PreVIous studies revealed that Collagen VI protects neurons from the toxicity of amyloid-βpeptides and from UV-induced damage. However, the physiological role of this protein in the central nervous system (CNS) remains unknown. Here, we established primary neural cultures from murine cortex and hippocampus, and carried out in VItro and in VIvo studies in wild-type and Collagen VI null (Col6a1-/-) mice. Col6a1-/- neural cultures displayed an increased incidence of spontaneous apoptosis and higher vulnerability to oxidative stress, accompanied by altered regulation of autophagy with increased p62 protein levels and decreased LC3 lipidation. Analysis of brain sections confirmed increased apoptosis and abnormal regulation of autophagy in the CNS of Collagen VI-deficient animals. To investigate the in VIvo physiological consequences of these CNS defects, we carried out functional studies and found that motor and memory task performances were impaired in aged Col6a1-/-mice. These findings indicate that lack of Collagen VI leads to spontaneous apoptosis and defective autophagy in neural cells, and point at a protective role for this ECM protein in the CNS during physiological aging.
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Collagen VI at a glance.
Journal of cell science, 2015Co-Authors: Matilde Cescon, Francesca Gattazzo, Peiwen Chen, Paolo BonaldoAbstract:Collagen VI represents a remarkable extracellular matrix molecule, and in the past few years, studies of this molecule have revealed its involvement in a wide range of tissues and pathological conditions. In addition to its complex multi-step pathway of biosynthesis and assembly that leads to the formation of a characteristic and distinctive network of beaded microfilaments in the extracellular matrix, Collagen VI exerts several key roles in different tissues. These range from unique biomechanical roles to cytoprotective functions in different cells, including myofibers, chondrocytes, neurons, fibroblasts and cardiomyocytes. Indeed, Collagen VI has been shown to exert a surprisingly broad range of cytoprotective effects, which include counteracting apoptosis and oxidative damage, favoring tumor growth and progression, regulating autophagy and cell differentiation, and even contributing to the maintenance of stemness. In this Cell Science at a Glance article and the accompanying poster, we present the current knowledge of Collagen VI, and in particular, discuss its relevance in stemness and in preserVIng the mechanical properties of tissues, as well as its links with human disorders.
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Lack of Collagen VI Promotes Wound-Induced Hair Growth
The Journal of investigative dermatology, 2015Co-Authors: Peiwen Chen, Matilde Cescon, Paolo BonaldoAbstract:Collagen VI is an extracellular matrix molecule that is abundantly expressed in the skin. However, the role of Collagen VI in hair follicle growth is unknown. Here, we show that Collagen VI is strongly deposited in hair follicles, and is markedly upregulated by skin wounding. Lack of Collagen VI in Col6a1 −/− mice delays hair cycling and growth under physiological conditions, but promotes wound-induced hair regrowth without affecting skin regeneration. Conversely, addition of purified Collagen VI rescues the abnormal wound-induced hair regrowth in Col6a1 −/− mice. Mechanistic studies revealed that the increased wound-induced hair regrowth of Col6a1 −/− mice is triggered by activation of the Wnt/β-catenin signaling pathway, and is abolished by inhibition of this pathway. These findings highlight the essential relationships between extracellular matrix (ECM) and hair follicle regeneration, and suggest that Collagen VI could be a potential therapeutic target for hair loss and other skin-related diseases.
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Role of Collagen VI in peripheral nerves and wound-induced hair regrowth
2015Co-Authors: Peiwen ChenAbstract:Collagen VI is an extracellular matrix (ECM) molecule dynamically expressed in a variety of tissues, including peripheral nerves and skin. However, the role of Collagen VI in the peripheral nervous system (PNS) and hair follicle growth is yet unknown. The main focus of my PhD study was to investigate the role and the underlying mechanisms of Collagen VI in peripheral nerve myelination and function, in PNS regeneration, as well as in wound-induced hair growth. During the first year of my PhD, I focused on investigating the phenotype of peripheral nerve myelination and function in Collagen VI null (Col6a1–/–) mice. The data shows that Schwann cells, but not axons, contribute to Collagen VI deposition in peripheral nerves. Lack of Collagen VI in Col6a1–/– mice leads to hypermyelination VIa multiple signaling pathways, disorganized C-fibers in the PNS, impaired nerve conduction velocity, and sensorimotor dysfunction. These findings indicate that that Collagen VI is a critical component of PNS contributing to the structural integrity and proper function of peripheral nerves. The second part of my PhD work focused on investigating the role of Collagen VI in PNS under pathological conditions using nerve crush injury models, and revealed a novel mechanism of this ECM protein in modulating macrophage function. The results show that Collagen VI is critical for macrophage migration and polarization during peripheral nerve regeneration. Nerve injury induces a robust upregulation of Collagen VI, whereas lack of Collagen VI in Col6a1–/– mice delays peripheral nerve regeneration. In VItro studies demonstrated that Collagen VI promotes macrophage migration and polarization VIa AKT and PKA pathways. Col6a1–/– macrophages exhibit impaired migration abilities and reduced anti-inflammatory (M2) phenotype polarization, but are prone to skewing towards pro-inflammatory (M1) phenotype. In VIvo, macrophage recruitment and M2 polarization are impaired in Col6a1–/– mice after nerve injury. The delayed nerve regeneration of Col6a1–/– mice is induced by macrophage deficits and rejuvenated by transplantation of wild-type bone marrow cells. These results identify Collagen VI as a novel regulator for peripheral nerve regeneration by modulating macrophage function. In the last year of my PhD I moved my focus to skin homeostasis and investigated the role of Collagen VI in wound-induced hair regrowth. The data shows that Collagen VI is strongly deposited in hair follicles, and it is dramatically upregulated by skin wounding. Lack of Collagen VI in Col6a1–/– mice promotes wound-induced hair regrowth, but does not affect skin regeneration. Conversely, addition of purified Collagen VI rescues the abnormal wound-induced hair regrowth in Col6a1–/– mice. Mechanistic studies revealed that the increased wound-induced hair regrowth of Col6a1–/– mice is triggered by upregulation of Keratin 79 and activation of the Wnt/beta-catenin signaling pathway, and is abolished by inhibition of the Wnt/beta-catenin pathway. These findings highlight the essential relationships between ECM and hair follicle regeneration, and point at Collagen VI as a potential therapeutic target for hair loss. Altogether, the data I obtained during my PhD studies strongly support a key role of Collagen VI in peripheral nerves and wound-induced hair follicle growth, thus paVIng the way for future studies on ECM molecules in PNS and skin under physiological and pathological conditions.
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Collagen VI regulates peripheral nerve regeneration by modulating macrophage recruitment and polarization
Acta Neuropathologica, 2015Co-Authors: Peiwen Chen, Matilde Cescon, Gaia Zuccolotto, Lucilla Nobbio, Cristina Colombelli, Monica Filaferro, Giovanni Vitale, M. Laura Feltri, Paolo BonaldoAbstract:Macrophages contribute to peripheral nerve regeneration and produce Collagen VI, an extracellular matrix protein involved in nerve function. Here, we show that Collagen VI is critical for macrophage migration and polarization during peripheral nerve regeneration. Nerve injury induces a robust upregulation of Collagen VI, whereas lack of Collagen VI in Col6a1 ^− / − mice delays peripheral nerve regeneration. In VItro studies demonstrated that Collagen VI promotes macrophage migration and polarization VIa AKT and PKA pathways. Col6a1 ^− / − macrophages exhibit impaired migration abilities and reduced antiinflammatory (M2) phenotype polarization, but are prone to skewing toward the proinflammatory (M1) phenotype. In VIvo, macrophage recruitment and M2 polarization are impaired in Col6a1 ^− / − mice after nerve injury. The delayed nerve regeneration of Col6a1 ^− / − mice is induced by macrophage deficits and rejuvenated by transplantation of wild-type bone marrow cells. These results identify Collagen VI as a novel regulator for peripheral nerve regeneration by modulating macrophage function.
Matilde Cescon - One of the best experts on this subject based on the ideXlab platform.
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Collagen VI in healthy and diseased nervous system
Disease models & mechanisms, 2018Co-Authors: Ilaria Gregorio, Paolo Bonaldo, Paola Braghetta, Matilde CesconAbstract:Collagen VI is a major extracellular matrix protein exerting a number of functions in different tissues, spanning from biomechanical to regulatory signals in the cell surVIval processes, and playing key roles in maintaining the stemness or determining the differentiation of several types of cells. In the last couple of years, emerging findings on Collagen VI have led to increased interest in its role in the nervous system. The role of this protein in the peripheral nervous system was intensely studied and characterized in detail. Collagen VI acts as a regulator of Schwann cell differentiation and is required for preserVIng peripheral nerve myelination, function and structure, as well as for orchestrating nerve regeneration after injury. Although the role and distribution of Collagen VI in the peripheral nervous system is now well established, the role of this distinctive extracellular matrix component in the central nervous system, along with its links to human neurological and neurodegenerative disorders, remains an open field of investigation. In this ReVIew, we summarize and discuss a number of recent findings related to Collagen VI in the central and peripheral nervous systems. We further link these findings to different aspects of the protein that are relevant to human diseases in these compartments in order to proVIde a comprehensive overVIew of the roles of this key matrix component in the nervous system.
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Lack of Collagen VI promotes neurodegeneration by impairing autophagy and inducing apoptosis during aging.
Aging, 2016Co-Authors: Matilde Cescon, Peiwen Chen, Ilaria Gregorio, Silvia Castagnaro, Paolo BonaldoAbstract:Collagen VI is an extracellular matrix (ECM) protein with a broad distribution in different tissues and mostly deposited at the close periphery of the cell surface. PreVIous studies revealed that Collagen VI protects neurons from the toxicity of amyloid-βpeptides and from UV-induced damage. However, the physiological role of this protein in the central nervous system (CNS) remains unknown. Here, we established primary neural cultures from murine cortex and hippocampus, and carried out in VItro and in VIvo studies in wild-type and Collagen VI null (Col6a1-/-) mice. Col6a1-/- neural cultures displayed an increased incidence of spontaneous apoptosis and higher vulnerability to oxidative stress, accompanied by altered regulation of autophagy with increased p62 protein levels and decreased LC3 lipidation. Analysis of brain sections confirmed increased apoptosis and abnormal regulation of autophagy in the CNS of Collagen VI-deficient animals. To investigate the in VIvo physiological consequences of these CNS defects, we carried out functional studies and found that motor and memory task performances were impaired in aged Col6a1-/-mice. These findings indicate that lack of Collagen VI leads to spontaneous apoptosis and defective autophagy in neural cells, and point at a protective role for this ECM protein in the CNS during physiological aging.
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Collagen VI–NG2 axis in human tendon fibroblasts under conditions mimicking injury response
Matrix biology : journal of the International Society for Matrix Biology, 2016Co-Authors: Francesca Sardone, Luciano Merlini, Raimund Wagener, Matilde Cescon, Francesca Tagliavini, Stefano Squarzoni, Spartaco Santi, Francesco Traina, Nadir M. Maraldi, Paolo BonaldoAbstract:In response to injury, tendon fibroblasts are activated, migrate to the wound, and contribute to tissue repair by producing and organizing the extracellular matrix. Collagen VI is a microfibrillar Collagen enriched in the pericellular matrix of tendon fibroblasts with a potential regulatory role in tendon repair mechanism. We investigated the molecular basis of the interaction between Collagen VI and the cell membrane both in tissue sections and fibroblast cultures of human tendon, and analyzed the deposition of Collagen VI during migration and myofibroblast trans-differentiation, two crucial events for tendon repair. Tendon fibroblast displayed a Collagen VI microfibrillar network closely associated with the cell surface. Binding of Collagen VI with the cell membrane was mediated by NG2 proteoglycan, as demonstrated by in VItro perturbation of Collagen VI–NG2 interaction with a NG2-blocking antibody. Cultures subjected to wound healing scratch assay displayed Collagen VI–NG2 complexes at the trailing edge of migrating cells, suggesting a potential role in cell migration. In fact, the addition of a NG2-blocking antibody led to an impairment of cell polarization and delay of wound closure. Similar results were obtained after in VItro perturbation of Collagen VI extracellular assembly with the 3C4 anti-Collagen VI antibody and in Collagen VI-deficient tendon cultures of a Ullrich congenital muscular dystrophy patient carrying mutations in COL6A2 gene. Moreover, in VItro treatment with transforming growth factor β1 (TGFβ1) induced a dramatic reduction of NG2 expression, both at protein and mRNA transcript level, and the impairment of Collagen VI association with the cell membrane. Instead, Collagen VI was still detectable in the extracellular matrix in association with ED-A fibronectin and Collagen I, which were strongly induced by TGFβ1 treatment. Our findings reveal a critical role of the NG2 proteoglycan for the binding of Collagen VI to the surface of tendon fibroblasts. By interacting with NG2 proteoglycan and other extracellular matrix proteins, Collagen VI regulates fibroblasts behaVIor and the assembly of tendon matrix, thereby playing a crucial role in tendon repair.
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Collagen VI at a glance.
Journal of cell science, 2015Co-Authors: Matilde Cescon, Francesca Gattazzo, Peiwen Chen, Paolo BonaldoAbstract:Collagen VI represents a remarkable extracellular matrix molecule, and in the past few years, studies of this molecule have revealed its involvement in a wide range of tissues and pathological conditions. In addition to its complex multi-step pathway of biosynthesis and assembly that leads to the formation of a characteristic and distinctive network of beaded microfilaments in the extracellular matrix, Collagen VI exerts several key roles in different tissues. These range from unique biomechanical roles to cytoprotective functions in different cells, including myofibers, chondrocytes, neurons, fibroblasts and cardiomyocytes. Indeed, Collagen VI has been shown to exert a surprisingly broad range of cytoprotective effects, which include counteracting apoptosis and oxidative damage, favoring tumor growth and progression, regulating autophagy and cell differentiation, and even contributing to the maintenance of stemness. In this Cell Science at a Glance article and the accompanying poster, we present the current knowledge of Collagen VI, and in particular, discuss its relevance in stemness and in preserVIng the mechanical properties of tissues, as well as its links with human disorders.
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Lack of Collagen VI Promotes Wound-Induced Hair Growth
The Journal of investigative dermatology, 2015Co-Authors: Peiwen Chen, Matilde Cescon, Paolo BonaldoAbstract:Collagen VI is an extracellular matrix molecule that is abundantly expressed in the skin. However, the role of Collagen VI in hair follicle growth is unknown. Here, we show that Collagen VI is strongly deposited in hair follicles, and is markedly upregulated by skin wounding. Lack of Collagen VI in Col6a1 −/− mice delays hair cycling and growth under physiological conditions, but promotes wound-induced hair regrowth without affecting skin regeneration. Conversely, addition of purified Collagen VI rescues the abnormal wound-induced hair regrowth in Col6a1 −/− mice. Mechanistic studies revealed that the increased wound-induced hair regrowth of Col6a1 −/− mice is triggered by activation of the Wnt/β-catenin signaling pathway, and is abolished by inhibition of this pathway. These findings highlight the essential relationships between extracellular matrix (ECM) and hair follicle regeneration, and suggest that Collagen VI could be a potential therapeutic target for hair loss and other skin-related diseases.
Carsten G. Bönnemann - One of the best experts on this subject based on the ideXlab platform.
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Genetic and clinical findings in a Chinese cohort of patients with Collagen VI‐related myopathies
Clinical genetics, 2018Co-Authors: Yanbin Fan, Yun Yuan, Aijie Liu, Cuijie Wei, Haipo Yang, Xingzhi Chang, Suxia Wang, Carsten G. BönnemannAbstract:Collagen VI-related myopathy, caused by pathogenic variants in the genes encoding Collagen VI, represents a clinical continuum from Ullrich congenital muscular dystrophy (UCMD) to Bethlem myopathy (BM). Clinical data of 60 probands and their family members were collected and muscle biopsies of 26 patients were analyzed. COL6A1, COL6A2 and COL6A3 exons were analyzed by direct sequencing or next generation sequencing (NGS). Sixty patients were characterized by delayed motor milestones, muscle weakness, skin and joint changes with 40 UCMD and 20 BM. Muscle with biopsies revealed dystrophic changes and showed completely deficiency of Collagen VI or sarcolemma specific Collagen VI deficiency. We identified 62 different pathogenic variants in these 60 patients, with 34 were first reported while 28 were preVIously known; 72 allelic pathogenic variants in COL6A1 (25/72, 34.7%), COL6A2 (33/72, 45.8%) and COL6A3 (14/72, 19.4%). We also found somatic mosaic variant in the parent of 1 proband by personal genome machine amplicon deep sequencing for mosaicism. Here we proVIde clinical, histological and genetic eVIdence of Collagen VI-related myopathy in 60 Chinese patients. NGS is a valuable approach for diagnosis and accurate diagnosis proVIdes useful information for genetic counseling of related families.
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Pneumothoraces in Collagen VI-related dystrophy: a case series and recommendations for management.
ERJ open research, 2017Co-Authors: Kristin Fraser, Carsten G. Bönnemann, Scott Wong, A. Reghan Foley, Sameer Chhibber, Daniel J. Lesser, Carla Grosmann, Anne RutkowskiAbstract:Collagen VI-related dystrophy (Collagen VI-RD) is a rare neuromuscular condition caused by mutations in the COL6A1 , COL6A2 or COL6A3 genes. The phenotypic spectrum includes early-onset Ullrich congenital muscular dystrophy, adult-onset Bethlem myopathy and an intermediate phenotype. The disorder is characterised by distal hyperlaxity and progressive muscle weakness, joint contractures and respiratory insufficiency. Respiratory insufficiency is attributed to chest wall contractures, scoliosis, impaired diaphragmatic function and intercostal muscle weakness. To date, intrinsic parenchymal lung disease has not been implicated in the ineVItable respiratory decline of these patients. This series focuses on pneumothorax, an important but preVIously under-recognised disease manifestation of Collagen VI-RD. We describe two distinct clinical presentations within Collagen VI-RD patients with pneumothorax. The first cohort consists of neonates and children with a single pneumothorax in the setting of large intrathoracic pressure changes. The second group is made up of adult patients with recurrent pneumothoraces, associated with chest computed tomography scan eVIdence of parenchymal lung disease. We describe treatment challenges in this unique population with respect to expectant observation, tube thoracostomy and open pleurodesis. Based on this experience, we offer recommendations for early identification of lung disease in Collagen VI-RD and definitive intervention.
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G.P.20 Transcriptome profiling identifies key regulators of molecular pathogenesis in Collagen VI myopathies
Neuromuscular Disorders, 2012Co-Authors: Russell J. Butterfield, Carsten G. Bönnemann, Robert B. WeissAbstract:Abstract Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) are inherited disorders of Collagen VI characterized by progressive muscle weakness and a combination of joint hyperlaxity and joint contractures. Collagen VI is present at the interface of the basement membrane and the extracellular matrix where it plays an important role in muscle maintenance. Recently, a role for Collagen VI has been demonstrated in the regulation of cellular homeostasis including stress responses mediated through the mitochondrial permeability transition pore (mPTP) and autophagy pathways. We hypothesize that fundamental cellular defects resulting from dysfunctional Collagen VI will be reflected in patient derived dermal fibroblasts and approachable using a systems biological approach. In this study we used transcriptional profiling to identify key pathways mediating the cellular response to mutations in Collagen VI. We used an RNA-Seq approach on the Illuminia, HiSeq platform to deeply sequence poly (A) purified transcripts from cultured fibroblast from UCMD patients and healthy controls. We quantified differential expression levels and assessed alternative splicing and isoform switching. Among the most significantly down-regulated genes in UCMD patients is ATG13, an important initiator of autophagy. In contrast, APAF1, an important initiator of apoptosis was among the most up-regulated transcripts in UCMD patients. These data are consistent with work in animal models suggesting the presence of dysregulated autophagy and apoptosis pathways in Collagen VI deficiency. Furthermore transcriptome profiling including gene-set analysis and determination of differential expression and alternative splicing in fibroblasts will identify cellular pathways important in pathogenesis. Identification of differentially expressed and regulated genes in UCMD will proVIde new targets for development of therapies as well as potential biomarkers to assess the efficacy of treatments.
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The Collagen VI-related myopathies: muscle meets its matrix
Nature reviews. Neurology, 2011Co-Authors: Carsten G. BönnemannAbstract:The Collagen VI-related myopathy known as Ullrich congenital muscular dystrophy is an early-onset disease that combines substantial muscle weakness with striking joint laxity and progressive contractures. Patients might learn to walk in early childhood; however, this ability is subsequently lost, concomitant with the development of frequent nocturnal respiratory failure. Patients with intermediate phenotypes of Collagen VI-related myopathy display a lesser degree of weakness and a longer period of ambulation than do indiVIduals with Ullrich congenital muscular dystrophy, and the spectrum of disease finally encompasses mild Bethlem myopathy, in which ambulation persists into adulthood. Dominant and recessive autosomal mutations in the three major Collagen VI genes-COL6A1, COL6A2, and COL6A3-can underlie this entire clinical spectrum, and result in deficient or dysfunctional microfibrillar Collagen VI in the extracellular matrix of muscle and other connective tissues, such as skin and tendons. The potential effects on muscle include progressive dystrophic changes, fibrosis and eVIdence for increased apoptosis, which potentially open avenues for pharmacological intervention. Optimized respiratory management, including noninvasive nocturnal ventilation together with careful orthopedic management, are the current mainstays of treatment and have already led to a considerable improvement in life expectancy for children with Ullrich congenital muscular dystrophy.
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Zebrafish Models of Collagen VI Related Myopathies
Human molecular genetics, 2010Co-Authors: William R. Telfer, A.s. Busta, Carsten G. Bönnemann, Eva L. Feldman, James J. DowlingAbstract:Collagen VI is an integral part of the skeletal muscle extracellular matrix, proVIding mechanical stability and facilitating matrix-dependent cell signaling. Mutations in Collagen VI result in either Ullrich congenital muscular dystrophy (UCMD) or Bethlem myopathy (BM), with UCMD being clinically more severe. Recent studies demonstrating increased apoptosis and abnormal mitochondrial function in Col6a1 knockout mice and in human myoblasts have proVIded the first mechanistic insights into the pathophysiology of these diseases. However, how loss of Collagen VI causes mitochondrial dysfunction remains to be understood. Progress is hindered in part by the lack of an adequate animal model for UCMD, as knockout mice have a mild motor phenotype. To further the understanding of these disorders, we have generated zebrafish models of the Collagen VI myopathies. Morpholinos designed to exon 9 of col6a1 produced a severe muscle disease reminiscent of UCMD, while ones to exon 13 produced a milder phenotype similar to BM. UCMD-like zebrafish have increased cell death and abnormal mitochondria, which can be attenuated by treatment with the proton pump modifier cyclosporin A (CsA). CsA improved the motor deficits in UCMD-like zebrafish, but failed to reverse the sarcolemmal membrane damage. In all, we have successfully generated the first vertebrate model matching the clinical severity of UCMD and demonstrated that CsA proVIdes phenotypic improvement, thus corroborating data from knockout mice supporting the use of mitochondrial permeability transition pore modifiers as therapeutics in patients, and proVIding proof of principle for the utility of the zebrafish as a powerful preclinical model.