Modulating the extracellular matrix to treat wound healing defects in Ehlers-Danlos syndrome.

Classic Ehlers-Danlos syndrome (cEDS) is a genetic disorder of the connective tissue that is characterized by mutations in genes coding type V collagen. Wound healing defects are characteristic of cEDS and no therapeutic strategies exist. Herein we describe a murine model of cEDS that phenocopies wound healing defects seen in humans. Our model features mice with conditional loss of in fibroblasts (Col5a1CKO). This model shows that an abnormal extracellular matrix (ECM) characterized by fibrillar disarray, altered mechanical properties, and decreased collagen deposition contribute to the wound healing defect. The cEDS animals exhibit decreased expression of epidermal genes and increased inflammation. Finally, we demonstrate that inhibiting mechanosensitive integrin signaling or by injecting wild-type (WT) fibroblasts into cEDS animals enhances epidermal gene expression, decreases inflammation, and augments wound closure. These findings suggest that cell delivery and/or blocking integrin signaling are potentially therapeutic strategies to rescue wound healing defects in cEDS.