Future Directions: The Known and Unknown Roles of Hair-Follicle Stem Cell Types

Abstract

Our laboratory has discovered that the hair follicle has both pluripotent and monopotent stem cells. We observed that nestin, a protein marker for neural stem cells, is also expressed in a population of hair-follicle stem cells and their immediate, differentiated progeny. The green fluorescent protein (GFP), whose expression is driven by the nestin regulatory element in transgenic mice (ND-GFP mice), served to mark hair-follicle stem cells and could be used to trace their fate. The ND-GFP hair-follicle stem cells are positive for the stem cell marker CD34 but negative for keratinocyte marker keratin 15, suggesting their relatively undifferentiated state. We have shown that the nestin-expressing hair-follicle stem cells can differentiate into neurons, glia, keratinocytes, smooth muscle cells, and melanocytes in vitro. In vivo studies show that the nestin-­expressing hair-follicle stem cells can differentiate into blood vessels and neural tissue after transplantation to the subcutis of nude mice. Nestin-expressing hair-follicle stem cells implanted into the gap region of severed sciatic or tibial nerves greatly enhance the rate of nerve regeneration and the restoration of nerve function. When transplanted to the severed peripheral nerves or spinal cord of the mice, the nestin-expressing follicle cells transdifferentiate largely into Schwann cells, which are known to support neuron regrowth. The transplanted mice regain the ability to walk normally. The nestin-expressing hair-follicle stem cells are pluripotent and provide an effective, accessible, autologous source of stem cells for the treatment of peripheral nerve injury and appear to be a paradigm for adult stem cells. We have observed that both the mouse and human hair follicles also contain nestin-negative, keratin-15-positive stem cells that form only keratinocytes as well as the pluripotent nestin-positive keratin-15-negative stem cells. A major question in stem cell and hair-follicle biology is: “What are the main roles of these two types of stem cells in the hair follicle?” Our future understanding of the role of the stem cell types in the hair follicle is a promising approach to study hair growth and aging.