Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-669899f699-chc8l Total loading time: 0 Render date: 2025-05-06T02:42:45.765Z Has data issue: false hasContentIssue false

33 - Hair follicle and skin regeneration

from Part V - Animal models and clinical applications

Published online by Cambridge University Press:  05 February 2015

By
Makoto Takeo  and
Mayumi Ito
Edited by
Peter X. Ma
Makoto Takeo
Affiliation:
New York University
Mayumi Ito
Affiliation:
New York University
Peter X. Ma
Affiliation:
University of Michigan, Ann Arbor
Get access

Summary

Introduction

The skin is the largest organ in the body and constitutes the interface between the body’s internal organs and its external surroundings. It serves multiple functions, lending thermoregulation, structure, and insulation to the body, and preventing water loss, while also acting as a barrier against external pathogens (Elias and Friend, 1975). The skin also allows an individual to respond to the environment through the nerve endings that sense different stimuli such as touch, pressure, temperature, and pain. These functions are essential for an individual’s survival and are maintained owing to the skin’s ability for regeneration. Much evidence has shown that the presence of stem cells in the epidermis and hair follicles underlies skin regeneration. In this chapter, we will review how skin is maintained under homeostatic conditions and following injury, particularly focussing on the role of stem cells in the hair follicle.

Skin homeostasis

The skin epidermis (i.e. inter-follicular epidermis) is composed of keratinocytes that form stratified squamous epithelium. Throughout an individual’s lifetime, epidermal cells of the skin differentiate and migrate to the superficial layer of the epidermis where they are shed, while being continuously renewed by proliferating cells of the basal layer adjacent to the basement membrane (Figure 33.1) (Mackenzie, 1970; Potten 1974; Watt 2001). Cells in the basal layer of the epidermis are a heterogeneous population in terms of their gene expression (Tani et al., 2000), proliferation rate (Potten and Morris, 1988), and differentiation status (Kaur and Li, 2000). Keratin 14-expressing basal epidermal cells contain long-lived stem cells that contribute to wound healing as well as maintenance of the basal layer of the epidermis (Mascre et al., 2012). However, the specific location of the stem cell niche or markers of stem cells for the inter-follicular epidermis has not yet been identified (Clayton et al., 2007). The properties of epidermal stem cells, and whether stem cells play distinct roles from their progeny in the renewal of skin epidermis, remain unknown.

Type
Chapter
Information
Biomaterials and Regenerative Medicine , pp. 590 - 602
Publisher: Cambridge University Press
Print publication year: 2014

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Book purchase

Temporarily unavailable

References

Barrandon, Y. and Green, H. 1987. Three clonal types of keratinocyte with different capacities for multiplication. Proc. Nat. Acad. Sci. USA, 84, 2302–6.CrossRefGoogle ScholarPubMed
Barrientos, S., Stojadinovic, O., Golinko, M. S., Brem, H. and Tomic-Canic, M. 2008. Growth factors and cytokines in wound healing. Wound Repair Regen., 16, 585–601.CrossRefGoogle ScholarPubMed
Bickenbach, J. R. and Mackenzie, I. C. 1984. Identification and localization of label-retaining cells in hamster epithelia. J. Invest. Dermatol., 82, 618–22.CrossRefGoogle ScholarPubMed
Billingham, R. E. and Russell, P. S. 1956. Incomplete wound contracture and the phenomenon of hair neogenesis in rabbit’s skin. Nature, 177, 791–2.CrossRefGoogle Scholar
Blanpain, C., Lowry, W. E., Geoghegan, A., Polak, L. and Fuchs, E. 2004. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell, 118, 635–48.CrossRefGoogle ScholarPubMed
Botchkarev, V. A., Botchkareva, N. V., Nakamura, M. et al. 2001. Noggin is required for induction of the hair follicle growth phase in postnatal skin. FASEB J., 15, 2205–14.CrossRefGoogle ScholarPubMed
Braun, K. M., Niemann, C., Jensen, U. B. et al. 2003. Manipulation of stem cell proliferation and lineage commitment: visualisation of label-retaining cells in wholemounts of mouse epidermis. Development, 130, 5241–55.CrossRefGoogle ScholarPubMed
Breedis, C. 1954. Regeneration of hair follicles and sebaceous glands from epithelium of scars in the rabbit. Cancer Res., 14, 575–9Google ScholarPubMed
Brownell, I., Guevara, E., Bai, C. B., Loomis, C. A. and Joyner, A. L. 2011. Nerve-derived sonic hedgehog defines a niche for hair follicle stem cells capable of becoming epidermal stem cells. Cell Stem Cell, 8, 552–65.CrossRefGoogle ScholarPubMed
Chase, H. B., Rauch, R. and Smith, V. W. 1951. Critical stages of hair development and pigmentation in the mouse. Physiol. Zool., 24, 1–8.CrossRefGoogle ScholarPubMed
Clayton, E., Doupe, D. P., Klein, A. M. et al. 2007. A single type of progenitor cell maintains normal epidermis. Nature, 446, 185–9.CrossRefGoogle ScholarPubMed
Cotsarelis, G., Sun, T. T. and Lavker, R. M. 1990. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell, 61, 1329–37.CrossRefGoogle ScholarPubMed
Demehri, S. and Kopan, R. 2009. Notch signaling in bulge stem cells is not required for selection of hair follicle fate. Development, 136, 891–6.CrossRefGoogle Scholar
Diamond, I., Owolabi, T., Marco, M., Lam, C. and Glick, A. 2000. Conditional gene expression in the epidermis of transgenic mice using the tetracycline-regulated transactivators tTA and rTA linked to the keratin 5 promoter. J. Invest. Dermatol., 115, 788–94.CrossRefGoogle ScholarPubMed
Dry, F. W. 1926. The coat of the mouse (Mus musculus). J. Genet., 16, 287–340.CrossRefGoogle Scholar
Elias, P. M. and Friend, D. S. 1975. The permeability barrier in mammalian epidermis. J. Cell. Biol., 65, 180–91.CrossRefGoogle ScholarPubMed
Fan, C., Luedtke, M. A., Prouty, S. M. et al. 2011. Characterization and quantification of wound-induced hair follicle neogenesis using in vivo confocal scanning laser microscopy. Skin Res. Technol., 17, 387–97CrossRefGoogle ScholarPubMed
Garza, L. A., Yang, C. C., Zhao, T. et al. 2011. Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells. J. Clin. Invest., 121, 613–22.CrossRefGoogle ScholarPubMed
Greco, V., Chen, T., Rendl, M. et al. 2009. A two-step mechanism for stem cell activation during hair regeneration. Cell Stem Cell, 4, 155–69.CrossRefGoogle ScholarPubMed
Guha, U., Mecklenburg, L., Cowin, P. et al. 2004. Bone morphogenetic protein signaling regulates postnatal hair follicle differentiation and cycling. Am. J. Pathol., 165, 729–40.CrossRefGoogle ScholarPubMed
Horsley, V., Aliprantis, A. O., Polak, L., Glimcher, L. H. and Fuchs, E. 2008. NFATc1 balances quiescence and proliferation of skin stem cells. Cell, 132, 299–310.CrossRefGoogle ScholarPubMed
Hsu, Y. C., Pasolli, H. A. and Fuchs, E. 2011. Dynamics between stem cells, niche, and progeny in the hair follicle. Cell, 144, 92–105.CrossRefGoogle ScholarPubMed
Ito, M., Kizawa, K., Hamada, K. and Cotsarelis, G. 2004. Hair follicle stem cells in the lower bulge form the secondary germ, a biochemically distinct but functionally equivalent progenitor cell population, at the termination of catagen. Differentiation, 72, 548–57.CrossRefGoogle ScholarPubMed
Ito, M., Kizawa, K., Toyoda, M. and Morohashi, M. 2002. Label-retaining cells in the bulge region are directed to cell death after plucking, followed by healing from the surviving hair germ. J. Invest. Dermatol., 119, 1310–16.CrossRefGoogle ScholarPubMed
Ito, M., Liu, Y., Yang, Z. et al. 2005. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nature Med., 11, 1351–54.CrossRefGoogle Scholar
Ito, M., Yang, Z., Andl, T. et al. 2007. Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature, 447, 316–20.CrossRefGoogle ScholarPubMed
Jahoda, C. A. B., Horne, K. A. and Oliver, R. F. 1984. Induction of hair growth by implantation of cultured dermal papilla cells. Nature, 311, 560–2.CrossRefGoogle ScholarPubMed
Jensen, K. B., Collins, C. A., Nascimento, E. et al. 2009. Lrig1 expression defines a distinct multipotent stem cell population in mammalian epidermis. Cell Stem Cell, 4, 427–39.CrossRefGoogle ScholarPubMed
Jensen, K. B. and Watt, F. M. 2006. Single-cell expression profiling of human epidermal stem and transit-amplifying cells: Lrig1 is a regulator of stem cell quiescence. Proc. Nat. Acad. Sci. USA, 103, 11958–63.CrossRefGoogle ScholarPubMed
Jones, P. H., Simons, B. D. and Watt, F. M. 2007. Sic transit gloria: farewell to the epidermal transit amplifying cell?Cell Stem Cell, 1, 371–81.CrossRefGoogle ScholarPubMed
Jones, P. H. and Watt, F. M. 1993. Separation of human epidermal stem cells from transit amplifying cells on the basis of differences in integrin function and expression. Cell, 73, 713–24.CrossRefGoogle ScholarPubMed
Kaur, P. and Li, A. 2000. Adhesive properties of human basal epidermal cells: an analysis of keratinocyte stem cells, transit amplifying cells, and postmitotic differentiating cells. J. Invest. Dermatol., 11, 413–20.CrossRefGoogle Scholar
Kimura-Ueki, M., Oda, Y., Oki, J. et al. 2012. Hair cycle resting phase is regulated by cyclic epithelial FGF18 signaling. J. Invest. Dermatol., 132, 1338–45.CrossRefGoogle ScholarPubMed
Kligman, A. M. and Strauss, J. S. 1956. The formation of vellus hair follicles from human adult epidermis. J. Invest. Dermatol., 27, 19–23.CrossRefGoogle ScholarPubMed
Kobielak, K., Stokes, N., de la Cruz, J., Polak, L. and Fuchs, E. 2007. Loss of a quiescent niche but not follicle stem cells in the absence of bone morphogenetic protein signaling. Proc. Nat. Acad. Sci. USA, 104, 10063–8CrossRefGoogle Scholar
Kobayashi, K., Rochat, A. and Barrandon, Y. 1993. Segregation of keratinocyte colony-forming cells in the bulge of the rat vibrissa. Proc. Nat. Acad. Sci. USA, 90, 7391–5.CrossRefGoogle ScholarPubMed
Levy, V., Lindon, C., Harfe, B. D. and Morgan, B. A. 2005. Distinct stem cell populations regenerate the follicle and interfollicular epidermis. Dev. Cell, 9, 855–61.CrossRefGoogle ScholarPubMed
Liang, Y., Silva, K. A., Kennedy, V. and Sundberg, J. P. 2011. Comparisons of mouse models for hair follicle reconstitution. Exp. Dermatol., 20, 1011–15CrossRefGoogle ScholarPubMed
Lichti, U., Weinberg, W. C., Goodman, L. et al. 1993. In vivo regulation of murine: hair growth: insights from grafting defined cell populations onto nude mice. J. Invest. Dermatol., 101, 124S–129S.CrossRefGoogle ScholarPubMed
Liu, Y., Lyle, S., Yang, Z. and Cotsarelis, G. 2003. Keratin 15 promoter targets putative epithelial stem cells in the hair follicle bulge. J. Invest. Dermatol., 121, 963–8.CrossRefGoogle ScholarPubMed
Lo Celso, C., Prowse, D. M. and Watt, F. M. 2004. Transient activation of β-catenin signalling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours. Development, 131, 1787–99.CrossRefGoogle ScholarPubMed
Lowry, W. E., Blanpain, C., Nowak, J. A. 2005. Defining the impact of β-catenin/Tcf transactivation on epithelial stem cells. Genes Dev., 19, 1596–611.CrossRefGoogle ScholarPubMed
Lyle, S., Christofidou-Solomidou, M., Liu, Y. et al. 1998. The C8/144B monoclonal antibody recognizes cytokeratin 15 and defines the location of human hair follicle stem cells. J. Cell Sci., 111(21), 3179–88.Google ScholarPubMed
Mackenzie, I. C. 1970. Relationship between mitosis and the ordered structure of the stratum corneum in mouse epidermis. Nature, 226, 653–5.CrossRefGoogle ScholarPubMed
Mascré, G., Dekoninck, S., Drogat, B. 2012. Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature, 489, 257–62.CrossRefGoogle ScholarPubMed
Millar, S. E. 2002. Molecular mechanisms regulating hair follicle development. J. Invest. Dermatol., 118, 216–25.CrossRefGoogle ScholarPubMed
Morris, R. J., Liu, Y., Marles, L. et al. 2004. Capturing and profiling adult hair follicle stem cells. Nature Biotechnol., 22, 411–17.CrossRefGoogle ScholarPubMed
Morris, R. J. and Potten, C. S. 1994. Slowly cycling (label-retaining) epidermal cells behave like clonogenic stem cells in vitro. Cell Prolif., 27, 279–89.CrossRefGoogle ScholarPubMed
Muller-Rover, S., Handjiski, B., van der Veen, C. et al. 2001. A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages. J. Invest. Dermatol., 117, 3–15.CrossRefGoogle ScholarPubMed
Myung, P. and Ito, M. 2012. Dissecting the bulge in hair regeneration. J. Clin. Invest., 122, 448–54.CrossRefGoogle ScholarPubMed
Myung, P. S., Takeo, M., Ito, M. and Atit, R. P. 2013. Epithelial Wnt ligand secretion is required for adult hair follicle growth and regeneration. J. Invest. Dermatol., 133(1), 31–41.CrossRefGoogle ScholarPubMed
Nath, M., Offers, M., Hummel, M. and Seissler, J. 2011. Isolation and in vitro expansion of Lgr6-positive multipotent hair follicle stem cells. Cell Tissue Res., 344, 435–44.CrossRefGoogle ScholarPubMed
Nijhof, J. G., Braun, K. M., Giangreco, A. et al. 2006. The cell-surface marker MTS24 identifies a novel population of follicular keratinocytes with characteristics of progenitor cells. Development, 133, 3027–37.CrossRefGoogle ScholarPubMed
Nowak, J. A., Polak, L., Pasolli, H. A. and Fuchs, E. 2008. Hair follicle stem cells are specified and function in early skin morphogenesis. Cell Stem Cell, 3, 33–43.CrossRefGoogle ScholarPubMed
Oliver, R. F. 1967. The experimental induction of whisker growth in the hooded rat by implantation of dermal papillae. J. Embryol. Exp. Morphol., 18, 43–51.Google ScholarPubMed
Oshimori, N. and Fuchs, E. 2012. Paracrine TGF-β signaling counterbalances BMP-mediated repression in hair follicle stem cell activation. Cell Stem Cell, 10, 63–75.CrossRefGoogle ScholarPubMed
Parakkal, P. F. 1990. Catagen and telogen phases of the growth cycle. In Orfanos, C. E. and Happle, R., editors. Hair and Hair Diseases. Berlin: Springer-Verlag, pp. 99–116.CrossRefGoogle Scholar
Paus, R. 1998. Principles of hair cycle control. J. Dermatol., 25, 793–802.CrossRefGoogle ScholarPubMed
Paus, R. and Cotsarelis, G. 1999. The biology of hair follicles. New Engl. J. Med., 341, 491–7.CrossRefGoogle ScholarPubMed
Paus, R., Muller-Rover, S., Van Der Veen, C. et al. 1999. A comprehensive guide for the recognition and classification of distinct stages of hair follicle morphogenesis. J. Invest. Dermatol., 113, 523–32.Google ScholarPubMed
Plikus, M., Wang, W. P., Liu, J. et al. 2004. Morpho-regulation of ectodermal organs: integument pathology and phenotypic variations in K14-Noggin engineered mice through modulation of bone morphogenic protein pathway. Am. J. Pathol., 164, 1099–114.CrossRefGoogle ScholarPubMed
Plikus, M. V., Baker, R. E., Chen, C. C. et al. 2011. Self-organizing and stochastic behaviors during the regeneration of hair stem cells. Science, 332, 586–9.CrossRefGoogle ScholarPubMed
Plikus, M. V., Mayer, J. A., de la Cruz, D. et al. 2008. Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration. Nature, 451, 340–4.CrossRefGoogle ScholarPubMed
Potten, C. S. 1974. The epidermal proliferative unit: the possible role of the central basal cell. Cell Tissue Kinet., 7, 77–88.Google ScholarPubMed
Potten, C. S., Hume, W. J., Reid, P. and Cairns, J. 1978. Segregation of DNA in epithelial stem-cells. Cell, 15, 899–906.CrossRefGoogle ScholarPubMed
Potten, C. S. and Morris, R. J. 1988. Epithelial stem cells in vivo. J. Cell Sci. Suppl., 10, 45–62.CrossRefGoogle ScholarPubMed
Rabbani, P., Takeo, M., Chou, W. et al. 2011. Coordinated activation of Wnt in epithelial and melanocyte stem cells initiates pigmented hair regeneration. Cell, 145, 941–55.CrossRefGoogle ScholarPubMed
Reddy, S., Andl, T., Bagasra, A. et al. 2001. Characterization of Wnt gene expression in developing and postnatal hair follicles and identification of Wnt5a as a target of Sonic hedgehog in hair follicle morphogenesis. Mech. Dev., 107, 69–82.CrossRefGoogle ScholarPubMed
Romano, R. A., Smalley, K., Liu, S. and Sinha, S. 2010. Abnormal hair follicle development and altered cell fate of follicular keratinocytes in transgenic mice expressing DeltaNp63alpha. Development, 137, 1431–9.CrossRefGoogle ScholarPubMed
Schmidt-Ullrich, R. and Paus, R. 2005. Molecular principles of hair follicle induction and morphogenesis. Bioessays, 27, 247–61.CrossRefGoogle ScholarPubMed
Snippert, H. J., Haegebarth, A., Kasper, M. et al. 2010. Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin. Science, 327, 1385–9.CrossRefGoogle Scholar
Stefanato, C. M. 2010. Histopathology of alopecia: a clinicopathological approach to diagnosis. Histopathology, 56, 24–38CrossRefGoogle Scholar
Stenn, K. 2005. Exogen is an active, separately controlled phase of the hair growth cycle. J. Am. Acad. Dermatol., 52, 374–5.CrossRefGoogle ScholarPubMed
Straile, W. E. 1967. Dermal–epithelial interactions in sensory hair follicles. In Montagna, W. and Dobson, R., editors. Advances in Biology of Skin, Vol. 9 New York: Pergamon Press, pp. 369–91.Google Scholar
Tani, H., Morris, R. J. and Kaur, P. 2000. Enrichment for murine keratinocyte stem cells based on cell surface phenotype. Proc. Nat. Acad. Sci. USA, 26, 10960–5.CrossRefGoogle Scholar
Taylor, G., Lehrer, M. S., Jensen, P. J., Sun, T. T. and Lavker, R. M. 2000. Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell, 102, 451–61.CrossRefGoogle Scholar
Toyoshima, K. E., Asakawa, K., Ishibashi, N. et al. 2012. Fully functional hair follicle regeneration through the rearrangement of stem cells and their niches. Nature Commun., 17, 784.CrossRefGoogle Scholar
Trempus., C. S., Morris, R. J., Bortner, C. D. et al. 2003. Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34. J. Invest. Dermatol., 120, 501–11.Google ScholarPubMed
Tumbar, T., Guasch, G., Greco, V. et al. 2004. Defining the epithelial stem cell niche in skin. Science, 303, 359–63.CrossRefGoogle ScholarPubMed
Van Mater, D., Kolligs, F. T., Dlugosz, A. A. and Fearon, E. R. 2003. Transient activation of β-catenin signaling in cutaneous keratinocytes is sufficient to trigger the active growth phase of the hair cycle in mice. Genes Dev., 17, 1219–24.CrossRefGoogle ScholarPubMed
Vasioukhin, V., Degenstein, L., Wise, B. and Fuchs, E. 1999. The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. Proc. Nat. Acad. Sci. USA, 96, 8551–6.CrossRefGoogle ScholarPubMed
Vauclair, S., Nicolas, M., Barrandon, Y. and Radtke, F. 2005. Notch1 is essential for postnatal hair follicle development and homeostasis. Dev. Biol., 284, 184–93.CrossRefGoogle ScholarPubMed
Vidal, V. P., Chaboissier, M. C., Lutzkendorf, S. et al. 2005. Sox9 is essential for outer root sheath differentiation and the formation of the hair stem cell compartment. Curr. Biol., 15, 1340–51.CrossRefGoogle ScholarPubMed
Watt, F. M. 2001. Stem cell fate and patterning in mammalian epidermis. Curr. Opin. Genet. Dev., 11, 410–17.CrossRefGoogle ScholarPubMed
Yamamoto, N., Tanigaki, K., Han, H., Hiai, H. and Honjo, T. 2003. Notch/RBP-J signaling regulates epidermis/hair fate determination of hair follicular stem cells. Curr. Biol., 13, 333–8.CrossRefGoogle ScholarPubMed
Zhang, J., He, X. C., Tong, W. G. et al. 2006. Bone morphogenetic protein signaling inhibits hair follicle anagen induction by restricting epithelial stem/progenitor cell activation and expansion. Stem Cells, 24, 2826–39.CrossRefGoogle Scholar
Zhang, Y. V., Cheong, J., Ciapurin, N., McDermitt, D. J. and Tumbar, T. 2009. Distinct self-renewal and differentiation phases in the niche of infrequently dividing hair follicle stem cells. Cell Stem Cell, 53, 267–78.CrossRefGoogle Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×