1. Inherited DNA Repair Defects Disrupt the Structure and Function of Human Skin.
- Author
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Ruiz-Torres S, Brusadelli MG, Witte DP, Wikenheiser-Brokamp KA, Sauter S, Nelson AS, Sertorio M, Chlon TM, Lane A, Mehta PA, Myers KC, Bedard MC, Pal B, Supp DM, Lambert PF, Komurov K, Kovacic MB, Davies SM, and Wells SI
- Subjects
- Cell Differentiation, Child, DNA Repair, Humans, Skin, Carcinoma, Squamous Cell, Fanconi Anemia genetics
- 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., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2021
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