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Regeneration of epidermal appendages

One of the major challenges for skin substitutes and grafts is the restoration of epidermal appendages—hair follicles and sweat glands. These complex specialized structures originate during development through dermal–epidermal induction and do not normally regenerate postnatally. Their absence in healed skin injuries results in functional impairment—absence of hair and sebum production or the loss of thermoregulation, respectively. This challenge in tissue engineering is the focus of two ground-breaking manuscripts in this issue of Wound Repair and Regeneration. Ono et al. describe the de novo regeneration of hair follicles in a rat wound model by the implantation of cultured dermal fibroblasts transduced with morphogen genes BMP2 and Wnt3 delivered in combination with FGF2. Within 4 months, the healed tissue had mature follicular structures evenly spaced throughout the wounded region. The gross and microscopic evidence is very intriguing and should lead to development of novel bioengineering applications. In their landmark study, Sheng et al. describe the regeneration of functional sweat glands through the transplantation of human bone marrow mesenchymal stem cells tested first in nude mice, then in a series of five burn patients. They cultured the stem cells in the presence of isolated human eccrine glandular cells to induce a regenerative phenotype, then the stem cells were implanted into the wound tissue; autologous transplantation was used for the burn patients. After 2 months functional restoration of perspiration was demonstrated by biochemical analyses and sweat volume measurements, which further increased with time. Histologic examination showed regenerated eccrine glands although with some structural differences that will require further investigation. But this first demonstration of feasibility in human subjects to restore cutaneous sweat glands holds promise for exciting developments to come, in skin healing and in injuries of other tissues with loss of glandular function. Scarring is a significant and widespread medical concern that presents a barrier to complete healing because of the loss of specialized components such as epidermal appendages. The exploration of developmental genes and stem cells for tissue regeneration is rapidly evolving and these two papers exemplify the tremendous potential of this investigative pathway for human clinical benefit through regeneration of epidermal appendages and enhanced regain of function—a significant breakthrough for mitigation of scar. The landmark human clinical trial by Sheng et al. is a first step in what it is hoped will be the next stage of regenerative wound therapies, which build upon a solid foundation of basic research in developmental and stem cell biology to create clinical tools to achieve healing of a higher order.