Summary Paragraph Mammalian skin appendages, such as hair follicles and sweat glands, are complex mini-organs formed during skin development 1, 2 . As wounds heal, the resulting scar tissue lacks skin appendages. The clinical regeneration of skin appendages is an ongoing challenge 3, 4 . Skin epithelial tissues have been regenerated in vivo by cellular reprogramming 5, 6 , 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. Furthermore, 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 .

In vivoreprogramming of wound-resident cells generates skin with hair