Transgenic Stem Cells to Regenerate the Skin

Epidermolysis bullosa is a severe and often fatal genetic disease caused by mutations in the genes that encode laminin, the basement membrane glycoprotein. Patients who survive with this condition develop chronic wounds on the skin and mucosa, which deteriorate their quality of life, and may even cause skin cancer. Recently studies showed that autologous transgenic keratinocyte cultures are capable of regenerating an entire and functional epidermis in a seven-year-old boy suffering from a devastating form of this disease. Clonal screening of these cells showed that the human epidermis is not supported by equipotent progenitors, but by a limited number of long-lived stem cells, dubbed holoclones, that they can self-renew extensively under in vitro and in vivo conditions and generate progenitors that replace terminally differentiated keratinocytes. This study provides a model that can be applied to other gene and cellular therapies, which is a breakthrough in fighting life-threatening genetic diseases.
Gene therapy and stem cell treatment are often considered the future of medicine, but there have been many barriers to putting these approaches into practice. In fact, there are few examples of truly useful human stem cell therapies. In a recent article, Hirsch et al describe a successful example: the use of gene therapy to correct cells in a child who had a devastating genetic disease associated with skin blisters (doi: 10.1038 / nature24487).

The skin is made up of the epidermis, which acts as a barrier against the external environment, and the underlying dermis, in which the epidermis is firmly anchored, giving it elasticity and mechanical resistance. In epidermolysis bullosa disease, genetic mutations prevent normal epidermal resistance or anchoring, making the skin fragile. Mechanical stress and minor trauma cause epidermal fragmentation or shedding of the dermis, causing blisters and ulcers on the skin. This produces chronic, painful, and intractable wounds, and ultimately leads to skin cancer, infection, and sometimes death. Currently there is no cure.
The authors took this strategy much further. A seven-year-old boy who had an extremely severe form of epidermolysis bullosa caused by mutations in LAMB3 entered a hospital in a life-threatening condition, having lost almost all of his skin. A 4 cm2 biopsy was taken of an unaffected part of his skin, and the cells in this tissue were genetically corrected using a retroviral vector carrying LAMB3. The corrected cell population grew to obtain 0.85 m2 of transgenic epidermal grafts. They replaced 80% of the patient's skin with the grafts in three separate operations (Figure 1). After 21 months of follow-up, the boy seemed to have fully recovered, without blisters. His skin was resistant to stress and healed normally.