Nanomechanics of cell-derived matrices as a functional read-out in collagen VI-related congenital muscular dystrophies.

Abstract

Changes in the mechanical properties of the extracellular matrix (ECM) are a hallmark of disease. Due to its relevance, several <i>in vitro</i> models have been developed for the ECM, including cell-derived matrices (CDMs). CDMs are decellularized natural ECMs assembled by cells that closely mimic the <i>in vivo</i> stromal fibre organization and molecular content. Here, we applied atomic force microscopy-force spectroscopy (AFM-FS) to evaluate the nanomechanical properties of CDMs obtained from patients diagnosed with collagen VI-related congenital muscular dystrophies (COL6-RDs). COL6-RDs are a set of neuromuscular conditions caused by pathogenic variants in any of the three major COL6 genes, which result in deficiency or dysfunction of the COL6 incorporated into the ECM of connective tissues. Current diagnosis includes the genetic confirmation of the disease and categorization of the phenotype based on maximum motor ability, as no direct correlation exists between genotype and phenotype of COL6-RDs. We describe differences in the elastic modulus (<i>E</i>) among CDMs from patients with different clinical phenotypes, as well as the restoration of <i>E</i> in CDMs obtained from genetically edited cells. Results anticipate the potential of the nanomechanical analysis of CDMs as a complementary clinical tool, providing phenotypic information about COL6-RDs and their response to gene therapies.