ANRV288-CB22-14 ARI 28 September 2006 21:57Epidermal Stem Cellsof the SkinC´edric Blanpain and Elaine Fuchs∗Howard Hughes Medical Institute, The Rockefeller University, New York,New York 10021; email: [email protected]. Rev. Cell Dev. Biol. 2006. 22:339–73First published online as a Review inAdvance on July 11, 2006The Annual Review ofCell and Developmental Biology is online athttp://cellbio.annualreviews.orgThis article’s doi:10.1146/annurev.cellbio.22.010305.104357Copyrightc 2006 by Annual Reviews.All rights reserved1081-0706/06/1110-0339$20.00∗Corresponding author.Key Wordshair follicle, multipotency, self-renewal, cell fate determination,Wnt signaling, Bmp, cancerAbstractThe skin constantly renews itself throughout adult life, and the hairfollicle undergoes a perpetual cycle of growth and degeneration.Stem cells (SCs) residing in the epidermis and hair follicle ensurethe maintenance of adult skin homeostasis and hair regeneration,but they also participate in the repair of the epidermis after injuries.We summarize here the current knowledge of epidermal SCs of theadult skin. We discuss their fundamental characteristics, the meth-ods recently designed to isolate these cells, the genes preferentiallyexpressed in the multipotent SC niche, and the signaling pathwaysinvolved in SC niche formation, SC maintenance, and activation. Fi-nally, we speculate on how the deregulation of these pathways maylead to cancer formation.339Annu. Rev. Cell Dev. Biol. 2006.22:339-373. Downloaded from arjournals.annualreviews.orgby MASSACHUSETTS INSTITUTE OF TECHNOLOGY on 11/08/06. For personal use only.ANRV288-CB22-14 ARI 28 September 2006 21:57Matrix: proliferativecompartment of thegrowing hair folliclecontainingprogenitor cells thatterminallydifferentiate to giverise to the hair shaftor the channelsurrounding itContentsINTRODUCTION................. 340ESTABLISHMENT ANDSTRATIFICATION OF SKINEPITHELIUM .................. 340EMBRYONIC HAIR FOLLICLEMORPHOGENESIS AND THEADULT HAIR CYCLE .......... 343STEM CELLS WITHIN THEADULT SKIN EPITHELIUM . . . 344The Interfollicular FollicularEpidermis..................... 344The Bulge Stem Cell Niche....... 347SIGNALING AND STEM CELLFATE SPECIFICATION INTHE SKIN ...................... 352Wnt/β-Catenin Signaling. . ....... 352Shh Signaling .................... 357Bone Morphogenetic ProteinSignaling...................... 358Notch Signaling .................. 360CONCLUSIONS................... 362OTHER GENES IMPLICATED INSKIN STEM CELL BIOLOGY . . 362CONCLUSIONS................... 364INTRODUCTIONSkin and its appendages ensure a numberof critical functions necessary for animalsurvival. Skin protects animals from waterloss, temperature change, radiation, trauma,and infections, and it allows animals to per-ceive their environment through tactile sense.Through camouflage, the skin provides pro-tection against predators, and it also servesas decoration for social and reproductivebehavior.Adult skin is composed of a diverse orga-nized array of cells emanating from differentembryonic origins. In mammals, shortly af-ter gastrulation, the neurectoderm cells thatremain at the embryo surface become theepidermis, which begins as a single layer ofunspecified progenitor cells. During develop-ment, this layer of cells forms a stratified epi-dermis (sometimes called interfollicular epi-dermis), the hair follicles (HRs), sebaceousglands, and, in nonhaired skin, the apocrine(sweat) glands. Mesoderm-derived cells con-tribute to the collagen-secreting fibroblastsof the underlying dermis, the dermovascu-lature that supplies nutrients to skin, arrec-tor pili muscles that attach to each hair folli-cle (HF), the subcutaneous fat cells, and theimmune cells that infiltrate and reside in theskin. Neural crest–derived cells contribute tomelanocytes, sensory nerve endings of theskin, and the dermis of the head. Overall,approximately 20 different cell types residewithin the skin.In the adult, many different types of stemcells (SCs) function to replenish these vari-ous cell types in skin as it undergoes normalhomeostasis or wound repair. Some SCs (e.g.,those that replenish lymphocytes) reside else-where in the body. Others (e.g., melanoblastsand epidermal SCs) reside within the skin it-self. This review concentrates primarily onepidermal SCs, which possess two essentialfeatures common to all SCs: They are able toself-renew for extended periods of time, andthey differentiate into multiple lineages de-rived from their tissue origin (Weissman et al.2001).ESTABLISHMENT ANDSTRATIFICATION OF SKINEPITHELIUMMature epidermis is a stratified squamous ep-ithelium whose outermost layer is the skinsurface. Only the innermost (basal) layer ismitotically active. The basal layer produces,secretes, and assembles an extracellular matrix(ECM), which constitutes much of the under-lying basement membrane that separates theepidermis from the dermis. The most promi-nent basal ECM component is laminin5,which utilizes α3β1-integrin for its assembly.As cells leave the basal layer and move out-ward toward the skin surface, they withdrawfrom the cell cycle, switch off integrin andlaminin expression, and execute a terminal340 Blanpain·FuchsAnnu. Rev. Cell Dev. Biol. 2006.22:339-373. Downloaded from arjournals.annualreviews.orgby MASSACHUSETTS INSTITUTE OF TECHNOLOGY on 11/08/06. For personal use only.ANRV288-CB22-14 ARI 28 September 2006 21:57differentiation program. In the early stagesof producing spinous and granular layers,the program remains transcriptionally active.However, it culminates in the production ofdead flattened cells of the cornified layer(squames) that are sloughed from the skin sur-face, continually being replaced by inner cellsmoving outward (Figure 1).The major structural proteins of theepidermis are keratins, which assemble asobligate heterodimers into a network of10-nm keratin intermediate filaments (IFs)that connect to α6β4-integrin-containinghemidesmosomes that anchor the base of theepidermis to the laminin5-rich, assembledECM. Keratin IFs also connect to intercel-lular junctions called desmosomes, composedof a core of desmosomal cadherins. Together,these connections tokeratin IFs provide anex-tensive mechanical framework to the epithe-lium (reviewed in Omary et al. 2004). Thebasal layer is typified by the expression of ker-atins K5 and K14 (also K15 in the embryo),whereas the intermediate suprabasal (spinous)layers express K1 and K10. Desmosomes con-nected to