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

Abstract

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.

Engineering Cell–ECM–Material Interactions for Musculoskeletal Regeneration

“…Engineered muscle ECM is a crucial component of recently developed and highly accurate in vitro disease models, which are of significant interest as personalized test platforms for novel muscle-targeting therapeutics. Collagen VI- related dystrophies (COL6-RDs) are rare congenital neuromuscular dystrophies where alterations in one of the three collagen VI genes change the collagen’s incorporation into the ECM, severely impacting the mechanical coherence of the matrix [ 36 ]. COL6-RDs result in muscle weakness, proximal joint contractures, and distal hyperlaxity.…”

“…Disease markers were significantly increased in CDMs from COL6-RD patients compared to controls (CDMs derived from healthy patients). Additionally, higher Collagen VI and fibronectin alignment, length, width, and straightness were observed in control CDMs compared to patient-derived CDMs, suggesting the model successfully captured the matrix characteristics of COL6-RD [ 36 ]. This and other studies summarized elsewhere [ 37 ] hint towards a future of personalized disease models for identifying the most effective treatment for individual patients.…”

Boosting the Clinical Translation of Organ-on-a-Chip Technology

“…Indeed, several works have employed human-derived materials within OoC platforms to boost their clinical relevance, some of them fully-defined in composition [ 28 , 29 , 30 , 31 ]. Particularly, human-based matrices provide multiple advantages compared to traditional biomaterials, such as a native-like composition or the ability to recapitulate the fibrillary architecture and mechanical properties of the in vivo cell habitat [ 32 ]. A particular feature of these matrices is their remarkable ability to recover after being completely dehydrated; this can be very attractive for commercialization purposes, where the microfluidic device can be pre-integrated with a lyophilized matrix, which can be reconstituted prior to starting the assay at the clinical laboratory; this approach could decrease the complexity, time and cost of traditional OoC experiments.…”