Reprogramming Skin Cells with a Novel Transcription Factor Combination Aids Wound Healing

Researchers here show that reprogramming of mesenchymal cells present in wounded skin produces a population of epithelial progenitor cells that induce the creation of new hair follicles and sweat glands during the healing process. Mammalian skin does not normally regenerate these features, an issue that many research groups have sought to address. This is an interesting advance, to be added to some of the other approaches that are claimed to more completely regenerate injured skin.

Mammalian skin appendages, such as hair follicles and sweat glands, are complex mini-organs formed during skin development. As wounds heal, the resulting scar tissue lacks skin appendages. The clinical regeneration of skin appendages is an ongoing challenge. Skin epithelial tissues have been regenerated in vivo by cellular reprogramming, but the de novo generation of skin appendages has not previously been achieved.

Here, we show that transplantation of a type of epithelial cell and two types of mesenchymal cells, reprogrammed from adult mouse subcutaneous mesenchymal cells to mimic developing skin cells, resulted in the generation of skin-appendage-like structures. After recent advances in cellular reprogramming we have developed a method to generate skin epithelial tissues by in vivo reprogramming of wound-resident mesenchymal cells with four transcription factors (DNP63A, GRHL2, TFAP2A, and cMYC), resulting in cells with the ability to form stratified epithelia.

With the development of a new AAV serotype, in vivo reprogramming of wound-resident cells with the same reprogramming factors generates skin with de novo appendages in adult mice. These findings may provide new therapeutic avenues for skin regeneration and frequent aging-associated skin appendage disorders, such as hair loss and dry skin, and may extend to other tissues and organs. This study also provides the potential for de novo generation of complex organs in vivo.