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Regeneration of the entire human epidermis using transgenic stem cells

2017; Nature Portfolio; Volume: 551; Issue: 7680 Linguagem: Inglês

10.1038/nature24487

1476-4687

Tobias Hirsch, Tobias Rothoeft, Norbert Teig, Johann Bauer, Graziella Pellegrini, Laura De Rosa, Davide Scaglione, Julia Reichelt, Alfred Klausegger, Daniela Kneisz, Oriana Romano, Alessia Secone Seconetti, Roberta Contin, Elena Enzo, Irena Jurman, Sonia Carulli, Frank Jacobsen, Thomas Luecke, Marcus Lehnhardt, Meike Fischer, Maximilian Kueckelhaus, Daniela Quaglino, Michele Morgante, Silvio Bicciato, Sergio Bondanza, Michele De Luca,

Silk-based biomaterials and applications

Junctional epidermolysis bullosa (JEB) is a severe and often lethal genetic disease caused by mutations in genes encoding the basement membrane component laminin-332. Surviving patients with JEB develop chronic wounds to the skin and mucosa, which impair their quality of life and lead to skin cancer. Here we show that autologous transgenic keratinocyte cultures regenerated an entire, fully functional epidermis on a seven-year-old child suffering from a devastating, life-threatening form of JEB. The proviral integration pattern was maintained in vivo and epidermal renewal did not cause any clonal selection. Clonal tracing showed that the human epidermis is sustained not by equipotent progenitors, but by a limited number of long-lived stem cells, detected as holoclones, that can extensively self-renew in vitro and in vivo and produce progenitors that replenish terminally differentiated keratinocytes. This study provides a blueprint that can be applied to other stem cell-mediated combined ex vivo cell and gene therapies. Autologous transgenic epidermal stem cell cultures are used to reconstitute almost the entire epidermis of a patient with severe junctional epidermolysis bullosa. Patients with junctional epidermolysis bullosa (JEB) carry mutations in genes that encode components of the basement membrane, which ensures the integrity between the epidermis and the dermis, such as laminin-332. These mutations cause blistering of the skin and chronic wounds. Following initial treatment of an adult patient with a limited affected region, Michele De Luca and colleagues reconstruct the full epidermis of a 7-year-old patient with autologous transgenic cells transduced with a virus vector carrying the non-mutated form of laminin-322. The integration sites of the virus used for gene delivery provide a tracing tool ex vivo and in vivo and demonstrate that the human epidermis is sustained by a limited number of long-lived stem cells.