Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited blistering skin disorder caused by mutations in the COL7A1 gene-encoding type VII collagen (Col7), the major component of anchoring fibrils at the dermal-epidermal junction. Individuals with RDEB develop painful blisters and mucosal erosions, and currently, there are no effective forms of therapy. Nevertheless, some advances in patient therapy are being made, and cell-based therapies with mesenchymal and hematopoietic cells have shown promise in early clinical trials. To establish a foundation for personalized, gene-corrected, patient-specific cell transfer, we generated induced pluripotent stem (iPS) cells from three subjects with RDEB (RDEB iPS cells). We found that Col7 was not required for stem cell renewal and that RDEB iPS cells could be differentiated into both hematopoietic and nonhematopoietic lineages. The specific epigenetic profile associated with de-differentiation of RDEB fibroblasts and keratinocytes into RDEB iPS cells was similar to that observed in wild-type (WT) iPS cells. Importantly, human WT and RDEB iPS cells differentiated in vivo into structures resembling the skin. Gene-corrected RDEB iPS cells expressed Col7. These data identify the potential of RDEB iPS cells to generate autologous hematopoietic grafts and skin cells with the inherent capacity to treat skin and mucosal erosions that typify this genodermatosis.
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We thank Dr Gerry O’Sullivan for examination of teratomas, and Marianna Wong, Jess Lorenz, Trevor Keyler, and Pavlina Chuntova for preparing laboratory data. We are grateful to Dr John McGrath for stimulating discussions on developing therapies for RDEB. We would like to acknowledge the use of confocal microscope made available through an NCRR Shared Instrumentation Grant (#1 S10 RR16851). This study was supported in part by grants from DEBRA International, Epidermolysis Bullosa Research Fund, University of Minnesota Academic Health Center, and by the Liao Family Epidermolysis Bullosa Fund, Sarah Rose Mooreland Epidermolysis Bullosa Fund, and Children's Cancer Research Fund, Minneapolis, Minnesota.