Modulating the Extracellular Matrix to Treat Wound Healing Defects in Ehlers-Danlos Syndrome

Classic Ehlers Danlos syndrome (cEDS) is one of the most common genetic disorders of the connective tissue and musculoskeletal system characterized by mutations in genes encoding for type V collagen. Defects in wound healing constitute one of the most common and debilitating symptoms in individuals with cEDS but currently, no therapeutic strategies exist to attenuate wound healing defects in cEDS. We create a new murine model of cEDS, that remarkably phenocopies wound healing defects in human cEDS. Using this model, we show that an abnormal extracellular matrix (ECM) characterized by fibrillar disarray, altered mechanical properties and decreased collagen deposition contribute to the wound healing defect in cEDS. The cEDS animals exhibit decreased expression of epidermal genes and increased inflammation consistent with the human phenotype. We show that integrin expression is altered in wounds of cEDS animals and small molecule modulators of mechanosensitive integrin signaling attenuate wound healing defects. Finally, we demonstrate that rescuing extracellular matrix defects by injecting wild type fibroblasts into wounds of cEDS animals significantly enhances epidermal gene expression, decreases inflammation, augments wound closure and rescues defective wound repair. Taken together, these observations suggest that modulation of the extracellular matrix in Ehlers-Danlos syndrome either with small molecule inhibitors of mechanosensitive integrin signaling, or direct injection of wild type fibroblasts into the wound bed may have therapeutic potential for enhancing wound healing in cEDS. Overall design: Examination of mouse skin cell expression changes after wounding in: WT vs Col5a1 CKO at day 14 and day 19 WT vs Col5a1 CKO at day 14 with and without transfer of WT fibroblasts in Col5a1 CKO animals WT+vehicle vs Col5a1 CKO+vehicle or Col5a1 CKO+ cilengitide at day 14 (cil_rnaseq2.txt)