Inherited DNA Repair Defects Disrupt the Structure and Function of Human Skin
Authors
Sonya Ruiz-Torres, Marion G. Brusadelli, David P. Witte, Kathryn A. Wikenheiser-Brokamp, Sharon Sauter, Adam S. Nelson, Mathieu Sertorio, Timothy M. Chlon, Adam Lane Parinda A. Mehta, Kasiani C. Myers, Mary C. Bedard Bidisha Pal, Dorothy M.Supp, Paul F. Lambert, Kakajan Komurov, Melinda Butsch Kovacic, Stella M. Davies, Susanne I.Wells
Institution
Cincinnati Children’s Hospital Medical Center; University of Cincinnati
Country
United States
Year
2020
Journal
Cell Stem Cell
Abstract
Squamous cell carcinoma (SCC) is a global public health burden originating in epidermal stem and progenitor cells (ESPCs) of the skin and mucosa. To understand how genetic risk factors contribute to SCC, studies of ESPC biology are imperative. Children with Fanconi anemia (FA) are a paradigm for extreme SCC susceptibility caused by germline loss-of-function mutations in FA DNA repair pathway genes. To discover epidermal vulnerabilities, patient-derived pluripotent stem cells (PSCs) conditional for the FA pathway were differentiated into ESPCs and PSC-derived epidermal organotypic rafts (PSC-EORs). FA PSC-EORs harbored diminished cell-cell junctions and increased proliferation in the basal cell compartment. Furthermore, desmosome and hemidesmosome defects were identified in the skin of FA patients, and these translated into accelerated blistering following mechanically induced stress. Together, we demonstrate that a critical DNA repair pathway maintains the structure and function of human skin and provide 3D epidermal models wherein SCC prevention can now be explored.
Product use
Differentiation and culture of iPSC-derived keratinocytes