Characterization of new stem/progenitor cells in skin appendages

Stem cells have long term self-renewal potential and are capable of differentiating into a variety of different cell types. This persistence and multipotency is crucial for the maintenance of tissue during homeostasis and repair. Due to its extraordinary regenerative potential, understanding its maintenance and regulation will prove its usefulness in tissue regeneration and treating various disorders. Thus, scientists have been intensely searching for stem cells in various organs in hopes to understand and take advantage of their regenerative abilities. Among the different organs, the skin is the most easily accessible making it a good model to study stem cells and wound healing. Moreover, the skin is a complex organ containing a number of different “mini-organs”, skin appendages that are likely maintained by independent stem cell populations. Understanding the similarities and differences between these stem cell populations may not only reveal how they maintain and regulate independent appendages, but also how stem cells maintain their own regenerative potential. ❧ The skin contains a number of different skin appendages including hair follicles, sweat glands, and nails. Among these appendages, hair follicles and their stem cells have been the most well characterized while relatively little is known about the presence of stem cells in the sweat gland and nail appendages. Since stem cells must persist throughout life, they have been proposed to be slow cycling cells in order to preserve their self renewing potential and minimize DNA replication errors during cell division. Decades ago, a population of slow cycling label retaining cells (LRCs) was identified in the hair follicle bulge. Numerous subsequent studies have collectively shown that these bulge LRCs are the hair follicle stem cells required for hair follicle regeneration. Moreover, these hair follicle stem cells have been shown to participate in epidermal wound healing during injury. Given that sweat glands are also abundantly distributed in the skin, there is great interest and speculation on whether sweat gland cells can also contribute to wound healing. ❧ Using a K5 driven tetracycline regulated H2B-GFP transgenic system, we have identified distinct LRCs in the nails and sweat glands as putative new skin stem cells. More specifically, LRCs were localized to the ventral proximal fold of the nail and the acinar secretory region of sweat glands. Both nail and sweat gland LRCs were found in the basal layer expressing K15, a known hair follicle stem cells marker. Lineage tracing experiments demonstrate that the K15 cells can contribute long-term to their respective appendages, suggesting long-term self-renewal capabilities found in stem cells. Isolation of live nail and sweat gland LRCs allowed for gene expression profiling to reveal their molecular characteristics, where BMP pathway signaling genes were identified in both sweat gland and nail appendages. Furthermore, we demonstrate the functional requirement of Bmpr1a-mediate signaling in both appendages. Transplanting strips of nail LRCs showed a contribution of H2B-GFP cells to the nail structure. Similar to hair follicle stem cells, sweat gland LRCs can differentiate and contribute to the epidermis under prolonged wound healing conditions. In addition, transplantation of sweat gland cells suggests its plasticity in regenerating sweat glands as well as hair follicles. ❧ In conclusion, we have identified slow cycling LRCs in the sweat gland and nail skin appendages that showed stem cell characteristics. Isolation and characterization of these LRCs show that they share similarities to hair follicle stem cells, but are also unique in possessing their own features. Although more studies are needed for further characterization of these LRCs, these data may shed some light on putative stem cells markers for human nails and sweat glands in the future.