The skin interfollicular epidermis (IFE) is an organism's first line of defense against a harmful environment and physical damage. During homeostasis and wound repair, the IFE is rejuvenated constantly by IFE stem cells (SCs) that are capable of both proliferation and differentiation. However, the identity and behavior of IFE SCs remain controversial.
Recent Advances:
Two opposing theories exist regarding homeostasis of the IFE. On the basis of morphological and proliferative characteristics, one posits that the IFE is composed of a discrete epidermal proliferative unit comprised of ∼10 transit-amplifying (TA) cells and a centrally located SC in the basal layer. The other suggests that homeostasis of the IFE is maintained by a single progenitor population in the basal layer. A recent study has challenged these two apparently distinct models and demonstrated that the basal layer of the IFE contains both SCs and TA cells, which make distinct contributions to tissue homeostasis and repair. Moreover, phosphorylation levels of the transcription factor p63, the master regulator of the proliferative potential of epidermal SCs, can be used to distinguish self-renewing SCs from TA cells with more limited proliferative potential.
Critical Issues:
As technologies advance, IFE SCs can be identified at a single-cell level. Refinements of their identification and characterization are critical, not only for SC biology but also for the development of novel clinical applications.
Future Directions:
Understanding the signaling pathways that control self-renewal and differentiation of IFE SCs will aid in developing novel cell-based therapeutics targeting degenerative epidermal diseases and wound repair.
Get full access to this article
View all access options for this article.
References
1.
BlanpainC, FuchsE. Epidermal homeostasis: a balancing act of stem cells in the skin. Nature Rev Mol Cell Biol, 2009; 10:207.
2.
HoathSB, LeahyDG. The organization of human epidermis: functional epidermal units and phi proportionality. J Invest Dermatol, 2003; 121:1440.
3.
PottenCS, SaffhillR, MaibachHI. Measurement of the transit time for cells through the epidermis and stratum corneum of the mouse and guinea-pig. Cell Tissue Kinet, 1987; 20:461.
4.
CotsarelisG, SunTT, LavkerRM. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell, 1990; 61:1329.
5.
BraunKM, NiemannC, JensenUB, SundbergJP, Silva-VargasV, WattFM. Manipulation of stem cell proliferation and lineage commitment: visualisation of label-retaining cells in wholemounts of mouse epidermis. Development, 2003; 130:5241.
SchuijersJ, CleversH. Adult mammalian stem cells: the role of Wnt, Lgr5 and R-spondins. EMBO J, 2012; 31:2685.
9.
ItoM, LiuY, YangZ, NguyenJ, LiangF, MorrisRJ, CotsarelisG. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med, 2005; 11:1351.
10.
LevyV, LindonC, HarfeBD, MorganBA. Distinct stem cell populations regenerate the follicle and interfollicular epidermis. Dev Cell, 2005; 9:855.
11.
LevyV, LindonC, ZhengY, HarfeBD, MorganBA. Epidermal stem cells arise from the hair follicle after wounding. FASEB J, 2007; 21:1358.
12.
LangtonAK, HerrickSE, HeadonDJ. An extended epidermal response heals cutaneous wounds in the absence of a hair follicle stem cell contribution. J Invest Dermatol, 2006; 128:1311.
13.
MackenzieIC. Relationship between mitosis and the ordered structure of the stratum corneum in mouse epidermis. Nature, 1970; 226:653.
14.
PottenCS. The epidermal proliferative unit: the possible role of the central basal cell. Cell Tissue Kinet, 1974; 7:77.
15.
StrachanLR, GhadiallyR. Tiers of clonal organization in the epidermis: the epidermal proliferation unit revisited. Stem Cell Rev, 2008; 4:149.
ClaytonE, DoupéDP, KleinAM, WintonDJ, SimonsBD, JonesPH. A single type of progenitor cell maintains normal epidermis. Nature, 2007; 446:185.
18.
DoupéDP, KleinAM, SimonsBD, JonesPH. The ordered architecture of murine ear epidermis is maintained by progenitor cells with random fate. Dev Cell, 2010; 18:317.
19.
DoupéDP, AlcoleaMP, RoshanA, ZhangG, KleinAM, SimonsBD, JonesPH. A single progenitor population switches behavior to maintain and repair esophageal epithelium. Science, 2012; 337:1091.
20.
FuchsE, HorsleyV. Ferreting out stem cells from their niches. Nat Cell Biol, 2011; 13:513.
21.
MascréG, DekoninckS, DrogatB, YoussefKK, BrohéeS, SotiropoulouPA, SimonsBD, BlanpainC. Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature, 2012; 489:257.
22.
McCullochEA, TillJE. Perspectives on the properties of stem cells. Nat Med, 2005; 11:1026.
23.
GreenH. The birth of therapy with cultured cells. Bioessays, 2008; 30:897.
24.
BarrandonY, GreenH. Three clonal types of keratinocyte with different capacities for multiplication. Proc Natl Acad Sci USA, 1987; 84:2302.
25.
SuzukiD, SenooM. Increased p63 phosphorylation marks early transition of epidermal stem cells to progenitors. J Invest Dermatol, 2012; 132:2461.
26.
KaelinWG. The emerging p53 family gene family. J Natl Cancer Inst, 1999; 91:594.
27.
Van BokhovenH, MelinoG, CandiE, DeclercqW. p63, a story of mice and men. J Invest Dermatol, 2011; 131:1196.
28.
MillsAA, ZhengB, WangXJ, VogelH, RoopDR, BradleyA. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature, 1999; 398:708.
29.
YangA, SchweitzerR, SunD, KaghadM, WalkerN, BronsonRT, TabinC, SharpeA, CaputD, CrumC, McKeonF. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature, 1999; 398:714.
RomanoRA, SmalleyK, MagrawC, SernaVA, KuritaT, RaghavanS, SinhaS. ΔNp63 knockout mice reveal its indispensable role as a master regulator of epithelial development and differentiation. Development, 2012; 139:772.
32.
SuhEK, YangA, KettenbachA, BambergerC, MichaelisAH, ZhuZ, ElvinJA, BronsonRT, CrumCP, McKeonF. p63 protects the female germ line during meiotic arrest. Nature, 2006; 444:624.
33.
SuX, ChakravartiD, ChoMS, LiuL, GiYJ, LinYL, LeungML, El-NaggarA, CreightonCJ, SuraokarMB, WistubaI, FloresER. TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature, 2010; 467:986.
34.
SuX, GiYJ, ChakravartiD, ChanIL, ZhangA, XiaX, TsaiKY, FloresER. TAp63 is a master transcriptional regulator of lipid and glucose metabolism. Cell Metab, 2012; 16:511.
35.
YangA, KaghadM, WangY, GillettE, FlemingMD, DötschV, AndrewsNC, CaputD, McKeonF. p63, a p53 homolog at 3q27–29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell, 1998; 2:305.
36.
MangiulliM, VallettiA, CaratozzoloMF, TulloA, SbisàE, PesoleG, D'ErchiaAM. Identification and functional characterization of two new transcriptional variants of the human p63. Nucleic Acids Res, 2009; 37:6092.
37.
SenooM, PintoF, CrumCP, McKeonF. p63 is essential for the proliferative potential of stem cells in stratified epithelia. Cell, 2007; 129:523.
38.
JonesPH, WattFM. Separation of human epidermal stem cells from transit amplifying cells on the basis of differences in integrin function and expression. Cell, 1993; 73:713.
39.
CarrollDK, CarrollJS, LeongCO, ChengF, BrownM, MillsAA, BruggeJS, EllisenLW. p63 regulates an adhesion programme and cell survival in epithelial cells. Nat Cell Biol, 2006; 8:551.
40.
NguyenBC, LefortK, MandinovaA, AntoniniD, DevganV, Della GattaG, KosterMI, ZhangZ, WangJ, Tommasi di VignanoA, KitajewskiJ, ChiorinoG, RoopDR, MisseroC, DottoGP. Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes Dev, 2006; 20:1028.
41.
RossiM, AqeilanRI, NealeM, CandiE, SalomoniP, KnightRA, CroceCM, MelinoG. The E3 ubiquitin ligase Itch controls the protein stability of p63. Proc Natl Acad Sci USA, 2006; 103:12753.
42.
YiR, PoyMN, StoffelM, FuchsE. A skin microRNA promotes differentiation by repressing “stemness”Nature, 2008; 452:225.
43.
WestfallMD, JoynerAS, BarbieriCE, LivingstoneM, PietenpolJA. Ultraviolet radiation induces phosphorylation and ubiquitin-mediated degradation of ΔNp63αCell Cycle, 2005; 4:710.
44.
NoszczykBH, MajewskiST. p63 expression during normal cutaneous wound healing in humans. Plast Reconstr Surg, 2001; 108:1242.
45.
MorassoMI, Tomic-CanicM. Epidermal stem cells: the cradle of epidermal determination, differentiation and wound healing. Biol Cell, 2009; 97:173.
46.
StojadinovicO, BremH, VouthounisC, LeeB, FallonJ, StallcupM, MerchantA, GalianoRD, Tomic-CanicM. Molecular pathogenesis of chronic wounds: the role of beta-catenin and c-myc in the inhibition of epithelialization and wound healing. Am J Pathol, 2005; 167:59.
47.
SchäferM, WernerS. Transcriptional control of wound repair. Annu Re Cell Dev Biol, 2007; 23:69.
48.
WuN, RollinJ, MasseI, LamartineJ, GidrolX. p63 regulates human keratinocyte proliferation via MYC-regulated gene network and differentiation commitment through cell adhesion-related gene network. J Biol Chem, 2012; 287:5627.
