Frontiers in Bioengineering and Biotechnology (Apr 2022)

Personalized in vitro Extracellular Matrix Models of Collagen VI-Related Muscular Dystrophies

  • Enrico Almici,
  • Enrico Almici,
  • Enrico Almici,
  • Vanessa Chiappini,
  • Vanessa Chiappini,
  • Vanessa Chiappini,
  • Arístides López-Márquez,
  • Arístides López-Márquez,
  • Carmen Badosa,
  • Carmen Badosa,
  • Blanca Blázquez,
  • Blanca Blázquez,
  • David Caballero,
  • David Caballero,
  • David Caballero,
  • Joan Montero,
  • Daniel Natera-de Benito,
  • Daniel Natera-de Benito,
  • Andrés Nascimento,
  • Andrés Nascimento,
  • Andrés Nascimento,
  • Mònica Roldán,
  • Anna Lagunas,
  • Anna Lagunas,
  • Cecilia Jiménez-Mallebrera,
  • Cecilia Jiménez-Mallebrera,
  • Cecilia Jiménez-Mallebrera,
  • Cecilia Jiménez-Mallebrera,
  • Josep Samitier,
  • Josep Samitier,
  • Josep Samitier

DOI
https://doi.org/10.3389/fbioe.2022.851825
Journal volume & issue
Vol. 10

Abstract

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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.

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