The Skin(ny) on Regenerating the Largest Organ to Save a Patient's Life

Junctional Epidermolysis Bullosa (JEB) is a severe, often lethal genetic disease caused by mutations in genes encoding the basement membrane component laminin-332. Surviving JEB patients develop chronic skin and mucosa wounds, 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 7-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 human epidermis is not sustained by equipotent progenitors, but by a limited number of long-lived stem cells, detected as holoclones, able to extensively self-renew in vitro and in vivo and to 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.