Regeneration of an Entire Functional Epidermis by Transgenic Epidermal Stem Cell Transplants
Maximilian Kueckelhaus, M.D.1, Tobias Rothoeft, M.D.2, Norbert Teig, M.D.2, Frank Jacobsen, Ph.D.1, Marcus Lehnhardt, M.D.1, Graziella Pellegrini, Ph.D.3, Michele De Luca, M.D.4, Tobias Hirsch, M.D.1.
1University Hospital Bergmannsheil, Bochum, Germany, 2University Hospital St. Josefs, Bochum, Germany, 3University of Modena and Reggio Emilia of Modena and Reggio Emilia, Modena, Italy, 4University of Modena and Reggio Emilia, Modena, Italy.
PURPOSE: We recently performed the regeneration of almost an entire human epidermis by transplantation of genetically modified epidermal stem cells in a 7-year-old patient suffering from terminal Junctional Epidermolysis Bullosa (JEB). JEB is caused by mutations of genes encoding for basement membrane components, LAMB3 in this case, leading to severe skin lesions with often lethal outcome.
METHODS: Epidermal stem cells were procured via skin biopsy and transduced using a retroviral vector expressing the full-length LAMB3 cDNA. The transduced stem cells were cultured using a modified culture protocol providing an optimal environment for the preservation of most potent epidermal stem cells, termed holoclones. We then transplanted 0,85m2 of autologous transgenic keratinocyte cultures. We performed a 2-year follow-up with clonal tracing and in-depth skin structure assessment using skin biopsies and optical coherence tomography. We also tested skin physiology and mechanical stress resistance. RESULTS: We regenerated 80% of the child's epidermis with autologous transgenic keratinocytes. Clonal tracing demonstrated, for the first time in humans, that the new epidermis was sustained by a finite number of holoclones. Two years after transplant, the patient demonstrated a high quality skin enabling a full range of motion, sebum production, and partial hair growth. Transepidermal water loss and skin elasticity were comparable to healthy skin. CONCLUSION: We show evidence for a high quality functional epidermis that is sustained by a finite number of highly regenerative stem cells. Besides providing the first potential cure for JEB, this technology may enable further treatments, such as skin regeneration after burns.
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