Abnormal extracellular matrix deposition by fascial fibroblasts underlies the connective tissue pathology in the disease Radial Dysplasia

Fibroblast cells are broadly distributed throughout the body and play instructive roles in tissue development and homeostasis. Defects in fibroblast function have been associated with developmental disorders, cancer and inflammatory disease. Our results reveal a previously unappreciated defect of fascial fibroblasts in patients with the upper limb congenital abnormality, Radial Dysplasia (RD). We identify compositional abnormalities in the extracellular matrix secreted by RD fascia-derived fibroblasts and provide an explanation for the consequent disorganisation and altered material properties of RD fascia and how this may impact disease pathology and patients' response to treatment. We show the abnormalities of RD fascial fibroblasts are reversible in vitro and identify a pathway with therapeutic potential to treat the soft tissue defects associated with RD. More broadly, our results have implications for understanding how heterogeneous tissue-resident fibroblast populations and the ECM they secrete contribute to normal tissue formation, homeostasis and disease.