Article Type : Commentary from the Editorial Board

Hair Follicles and Their Potential in Wound Healing. Katherine L. Baquerizo Nole, M.D Robert S. Kirsner, M.D., Ph.D. Author Affiliation: Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida. Financial Disclosure: None reported Correspondence: Robert S. Kirsner, MD, PhD Department of Dermatology and Cutaneous Surgery University of Miami Miller School of Medicine 1600 NW 10th Ave, RMSB, Room 2023-A, Miami, Florida 33136 Telephone 305 243 4472 Fax 305 243 6191 [email protected]

Chronic wounds affect more than 6 million people annually in the US 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 signaling to HF neogenesis, and then providing examples of currently available hair-related therapies in wound management. The Importance of Follicular Stem Cells in Wound Healing HF display a unique, lifelong cycling process, regulated by complex ectodermalmesenchymal 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 reepithelization 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). This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/exd.12607 This article is protected by copyright. All rights reserved.

For more details see Table 1 and Figure 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 center of large wounds has been described after wound reepithelization. Despite the fact that neo HF have a prominent Krt15+ population, the origin of these neo HF and their stem cells (SC) do not appear to come from Krt15+ bulge SC of preexisting 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 (6). 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. recently reported in Exp Dermatol (7) 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. Hair Follicles and Wound Healing 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 non-hair bearing or less hairy areas, only selected reports utilizing hairderived 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 (8). More recently Lough et al, 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 (9). 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. (10) previously compared punch skin grafts derived from hair-bearing skin to non treated 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 hairbearing 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 non hair-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 (11). 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

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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 aging does not alter the density of FSC, nor does it decrease the bulge cell DNA content per hair follicle; this compares favorably to the likely reduced proliferative capacity of the interfollicular epidermis (8). 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. Acknowledgement KLBN wrote the initial draft and RSK reviewed the manuscript. Conflicts of interest The authors declare no conflict of interest.

References: 1. Sen CK, Gordillo GM, Roy S, et al. Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen. 2009;17:763-71. 2. Mokos ZB, Mosler EL. Advances in a rapidly emerging field of hair follicle stem cell research. Coll Antropol. 2014;38:373-8. 3. Jimenez F, Poblet E, Izeta A. Reflections on how wound healing-promoting effects of the hair follicle can be translated into clinical practice. Exp Dermatol. 2014. 4. Plikus MV, Gay DL, Treffeisen E, et al. Epithelial stem cells and implications for wound repair. Semin Cell Dev Biol. 2012;23:946-53. 5. Gharzi A, Reynolds AJ, Jahoda CA. Plasticity of hair follicle dermal cells in wound healing and induction. Exp Dermatol. 2003;12:126-36. 6. Snippert HJ, Haegebarth A, Kasper M, et al. Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin. Science. 2010;327:1385-9. 7. Plikus MV, Guerrero-Juarez CF, Treffeisen E, et al. Epigenetic control of skin and hair regeneration after wounding. Exp Dermatol. 2014. This article is protected by copyright. All rights reserved.

8. Tausche AK, Skaria M, Bohlen L, et al. An autologous epidermal equivalent tissueengineered from follicular outer root sheath keratinocytes is as effective as splitthickness skin autograft in recalcitrant vascular leg ulcers. Wound Repair Regen. 2003;11:248-52. 9. Lough DM, Yang M, Blum A, et al. Transplantation of the LGR6+ epithelial stem cell into full-thickness cutaneous wounds results in enhanced healing, nascent hair follicle development, and augmentation of angiogenic analytes. Plast Reconstr Surg. 2014;133:579-90. 10. Jimenez F, Garde C, Poblet E, et al. A pilot clinical study of hair grafting in chronic leg ulcers. Wound Repair Regen. 2012;20:806-14. 11. Kirsner RS, Mata SM, Falanga V, et al. Split-thickness skin grafting of leg ulcers. The University of Miami Department of Dermatology's experience (1990-1993). Dermatol Surg. 1995;21:701-3. 12. Purba TS, Haslam IS, Poblet E, et al. Human epithelial hair follicle stem cells and their progeny: current state of knowledge, the widening gap in translational research and future challenges. Bioessays. 2014;36:513-25.

LEGEND FIGURE 1. HAIR FOLLICLE STEM CELLS. Diagram of hair follicle with the stem cells populations relevant to wound healing. IFSC: Interfollicular stem cells. TABLE 1. HAIR FOLLICLE STEM CELLS AND FUNCTIONS.




Physiological functions(4) Contribution to infundibulum and sebaceous glands lineage


Basal inter follicular epidermis

Junctional zone


No literature found




Bulge and Close association to secondary hair perifollicular sensory germ nerve endings

Epidermal and sebaceous glands maintenance

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Wound healing functions(4) Long-lasting progeny contribution to interfollicular epidermis after wounding. Long-lasting progeny contribution after skin wounding Contribution of long-lasting progeny after skin wounding




Reconstitute all epithelial lineages of HF, interfollicular epidermis, and sebaceous glands

SC: Stem cells HF: Hair follicles

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Early contribution to interfollicular epidermis after wounding

Hair follicles and their potential in wound healing.

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