Year: 2014
Type: article
Abstract: Chronic wounds affect more than 6 million people annually in the Unites States alone, and the cost to the healthcare system is an estimated $25 billion 1. Despite recent technology advances in tissue engineering and drugs, more cost-effective treatments are needed. With approximately 5 million hair follicles (HF) 2 continuously generating hair over the body, is it possible to harness this growth potential in wound management? Jimenez et al. 3 Exp Dermatol 2014 provide compelling reasons to engender hope, guiding us first through basic science research supporting the role of HF in wound healing, the influence of hair cycling, follicular stem cells (FSC) and signalling to HF neogenesis, and then providing examples of currently available hair-related therapies in wound management. Hair follicles display a unique, lifelong cycling process, regulated by complex ectodermal–mesenchymal interactions. HF phases include the anagen (rapid growth), catagen (apoptosis driven regression) and telogen (relative resting), and FSC play an important role in this process. FSC reside in different parts of the HF, and the importance of FSC in wound re-epithelization has been described as a dichotomic process, at least in mice. Initially, a rapid and transient influx of bulge FSC (Krt15+) contribute to early re-epithelization; these are later replaced by a long-lasting population from the isthmus (Lgr6+, Gli1+ and Lrig1+) 4. For more details, see Table 1 and Fig. 1. Additionally, Reynolds et al. in a previous issue of Exp Dermatol found that dermal sheath cells also have a FSC role. Both upper and lower dermal sheath cells are incorporated into the neodermis after skin wounding, but only dermal sheath cells from the lower dermis are assimilated into HF 5. Recently, HF neogenesis in the centre of large wounds has been described after wound re-epithelization. Despite the fact that neo-HF have a prominent Krt15+ population, the origin of these neo-HF and their stem cells (SC) does not appear to come from Krt15+ bulge SC of pre-existing hairs. The exact origins of these neo-HF and from which particular SC populations they originate are not clear, but cellular and molecular markers suggest that they are derived from Lgr6+ FSC 7. As generation of neo-HF is not solely an epithelial process, an intact dermal papillae is required for HF neogenesis, suggesting complex mesenchymal–epithelial interactions are at play 5. These complex mesenchymal–epithelial interactions are the types of interactions seen during wound repair. Plikus et al. 8 recently reported in Exp Dermatol that as opposed to the epigenetic regulation of the interfollicular epidermis, FSC exhibit a greater degree of flexibility in the generation of different hair cell types. This malleability supports the role of FSC in wound healing and highlights their potential for therapeutic benefit. As pointed out by Jimenez et al. 9, despite the increasing knowledge regarding the role of HF in wound healing and clinical observations that wounds in high hair density areas heal faster than those in nonhair-bearing or less hairy areas, only selected reports utilizing hair-derived treatments exist. Among these, the generation of epidermal autografts derived from outer root sheath (Epidex®; EurodermBiotec& Aesthetics, Stutgart, Germany) found comparable efficacy in treatment of recalcitrant leg ulcers to the well-established method of split-thickness-meshed skin grafting, with fewer patients having treatment failure 10. More recently, Lough et al. 11, using a murine model, transplanted Lgr6+ FSC in a hydrogel vehicle, comparing this to hydrogel alone, and found that wound beds that received Lgr6 FSC demonstrated increased epithelization, hair growth and angiogenesis. Although promising and supportive of the HF potential for wound healing, these technologies are not necessarily simple or inexpensive. In a more practical approach, Jimenez et al. 9 previously compared punch skin grafts derived from hair-bearing skin to nontreated areas in refractory leg ulcers. They reported superior healing with greater wound size reduction (27% vs. 7% at 18 weeks), improved granulation tissue appearance and wound border reactivation in the areas that received hair-bearing skin grafts. We have also seen improved healing with hair-bearing skin grafts, observing increased healing in wounds treated with skin grafts derived from hair-bearing areas (scalp) compared with skin grafts derived from nonhair-bearing (back) skin, and control areas (Baquerizo Nole et al. Submitted for Publication). Autologous skin grafts, often used in the treatment of refractory wounds, have a variable success. Never subjected to testing in a randomized fashion, meshed split-thickness skin grafts, for instance, have been reported to achieve healing in 50% to 75% of cases in large clinical series 12. Improvement of skin grafting techniques such as use of optimal donor tissue such as hair-bearing skin with high density of HF and FSC might be able to better promote healing rates without increasing donor site morbidity. HF may be ideal as skin grafting donor areas, given that hair-bearing skin heals rapidly with minimal scarring, and their potential superiority due to the presence of FSC. Given the perceived importance of FSC in healing, it is not surprising that the hair cycle phase influences wound healing, with faster healing with the use of HF in anagen phase as opposed to telogen phase 3. This suggests follicular grafting may be optimized to even a greater extent by taking hairs in anagen phase for grafting, perhaps identified by dermoscopy or other imaging techniques. As wounds increase in incidence and prevalence with age, it is important to note that ageing does not alter the density of FSC, nor does it decrease the bulge cell DNA content per hair follicle; this compares favourably to the likely reduced proliferative capacity of the interfollicular epidermis 10. Emerging technologies may improve cellular persistence of currently available allogeneic cellular tissue-engineered products, but this prolonged persistence may allow graft rejection to occur. Graft rejection is not typically a consequence of the current products. However, using lower dermal sheath cells may present a mechanism to bypass immune surveillance, as these cells are thought to be immune privileged 5. Thus, the use of allograft fibroblasts derived from the lower dermal sheath potentially may allow enhanced persistence without rejection. Given the great availability of FSC, easy access to tissue containing FSC and the advantages over interfollicular SC, therapeutic potential exists for a variety of conditions, including non/slow healing wounds, large wounds and epidermal depigmenting disorders, among others 2. Emerging research will further elucidate the role of HF in wound healing and perhaps create innovative technologies to improve healing or optimize existing therapies already in use. KLBN wrote the initial draft and RSK reviewed the manuscript. None reported. The authors have declared no conflicting interests.
Source: Experimental Dermatology
DOI: 10.1111/exd.12607
Institution: University of Miami
Language: English
Topic: Hair Growth and Disorders
Subfield: Urology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1993519399