Personalized in vitro Extracellular Matrix Models of Collagen VI-Related Muscular Dystrophies
Por:
Almici E, Chiappini V, López-Marquez A, Badosa-Gallego MC, Blázquez B, Caballero D, Montero J, Natera-de Benito D, Nascimento-Osorio A, Roldan-Molina M, Lagunas A, Jimenez-Mallebrera C and Samitier J
Publicada:
25 abr 2022
Ahead of Print:
25 abr 2022
Resumen:
Collagen VI-related dystrophies (COL6-RDs) are a group of rare congenital neuromuscular dystrophies that represent a continuum of overlapping clinical phenotypes that go from the milder Bethlem myopathy (BM) to the severe Ullrich congenital muscular dystrophy, for which there is no effective treatment. Mutations in one of the three Collagen VI genes alter the incorporation of this protein into the extracellular matrix (ECM), affecting the assembly and the structural integrity of the whole fibrillar network. Clinical hallmarks of COL6-RDs are secondary to the ECM disruption and include muscle weakness, proximal joint contractures, and distal hyperlaxity. Although some traits have been identified in patients' ECMs, a correlation between the ECM features and the clinical phenotype has not been established, mainly due to the lack of predictive and reliable models of the pathology. Herein, we engineered a new personalized pre-clinical model of COL6-RDs using cell-derived matrices (CDMs) technology to better recapitulate the complexity of the native scenario. We found that CDMs from COL6-RD patients presented alterations in ECM structure and composition, showing a significantly decreased Collagen VI secretion, especially in the more severe phenotypes, and a decrease in Fibrillin-1 inclusion. Next, we examined the Collagen VI-mediated deposition of Fibronectin in the ECM, finding a higher alignment, length, width, and straightness than in patients with COL6-RDs. Overall, these results indicate that CDMs models are promising tools to explore the alterations that arise in the composition and fibrillar architecture due to mutations in Collagen VI genes, especially in early stages of matrix organization. Ultimately, CDMs derived from COL6-RD patients may become relevant pre-clinical models, which may help identifying novel biomarkers to be employed in the clinics and to investigate novel therapeutic targets and treatments.
Filiaciones:
Almici E:
Nanobioengineering Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
Department of Electronic and Biomedical Engineering, University of Barcelona, Barcelona, Spain
Biomedical Research Networking, Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Madrid, Spain
Chiappini V:
Nanobioengineering Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
Department of Electronic and Biomedical Engineering, University of Barcelona, Barcelona, Spain
Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Torino, Italy
López-Marquez A:
Laboratorio de Investigación Aplicada en Enfermedades Neuromusculares, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Unidad de Patología Neuromuscular, Servicio de Neuropediatría, Hospital Sant Joan de Déu, Barcelona, Spain
Badosa-Gallego MC:
Laboratorio de Investigación Aplicada en Enfermedades Neuromusculares, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Unidad de Patología Neuromuscular, Servicio de Neuropediatría, Hospital Sant Joan de Déu, Barcelona, Spain
Blázquez B:
Nanobioengineering Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
Biomedical Research Networking, Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Madrid, Spain
Caballero D:
Nanobioengineering Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
Department of Electronic and Biomedical Engineering, University of Barcelona, Barcelona, Spain
Biomedical Research Networking, Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Madrid, Spain
Montero J:
Nanobioengineering Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
Natera-de Benito D:
Laboratorio de Investigación Aplicada en Enfermedades Neuromusculares, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Unidad de Patología Neuromuscular, Servicio de Neuropediatría, Hospital Sant Joan de Déu, Barcelona, Spain
Nascimento-Osorio A:
Laboratorio de Investigación Aplicada en Enfermedades Neuromusculares, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Unidad de Patología Neuromuscular, Servicio de Neuropediatría, Hospital Sant Joan de Déu, Barcelona, Spain
Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Madrid, Spain
Roldan-Molina M:
Unitat de Microscòpia Confocal i Imatge Cel·lular, Servei de Medicina Genètica i Molecular, Institut Pediàtric de Malalties Rares (IPER), Hospital Sant Joan de Déu, Barcelona, Spain
Lagunas A:
Nanobioengineering Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
Biomedical Research Networking, Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Madrid, Spain
Jimenez-Mallebrera C:
Laboratorio de Investigación Aplicada en Enfermedades Neuromusculares, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Unidad de Patología Neuromuscular, Servicio de Neuropediatría, Hospital Sant Joan de Déu, Barcelona, Spain
Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Madrid, Spain
Department of Genetics, Microbiology and Statistics, University of Barcelona, Barselona, Spain
Samitier J:
Nanobioengineering Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
Department of Electronic and Biomedical Engineering, University of Barcelona, Barcelona, Spain
Biomedical Research Networking, Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Madrid, Spain
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