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Cited by 320Hair Growth and DisordersSkin and Cellular Biology ResearchCancer Cells and Metastasis

The Epidermis Comprises Autonomous Compartments Maintained by Distinct Stem Cell Populations

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Page, Mahalia E., Lombard, Patrick, Ng, Felicia, Göttgens, Berthold, Jensen, Kim B.·2013·Cell Stem Cell
DOI 10.1016/j.stem.2013.07.010PMC PMC3793873
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Abstract

The complex anatomy of the epidermis contains multiple adult stem cell populations, but the extent to which they functionally overlap during homeostasis, wound healing, and tumor initiation remains poorly defined. Here, we demonstrate that Lrig1(+ve) cells are highly proliferative epidermal stem cells. Long-term clonal analysis reveals that Lrig1(+ve) cells maintain the upper pilosebaceous unit, containing the infundibulum and sebaceous gland as independent compartments, but contribute to neither the hair follicle nor the interfollicular epidermis, which are maintained by distinct stem cell populations. In contrast, upon wounding, stem cell progeny from multiple compartments acquire lineage plasticity and make permanent contributions to regenerating tissue. We further show that oncogene activation in Lrig1(+ve) cells drives hyperplasia but requires auxiliary stimuli for tumor formation. In summary, our data demonstrate that epidermal stem cells are lineage restricted during homeostasis and suggest that compartmentalization may constitute a conserved mechanism underlying epithelial tissue maintenance.

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  • The SG has been proposed to be replenished by distinct pools of stem cells or progenitors located in the HF or base of the SG.

    “The SG has been proposed to be replenished by distinct pools of stem cells or progenitors located in the HF or base of the SG3–7.”

    From Blimp1+ cells generate functional mouse sebaceous gland organoids in vitro (2019) · cites this paper as [6]

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References 51 · Cited by 320

Research works printed but not linked: 47

  1. Alcolea M.P. Jones P.H. Tracking cells in their native habitat: lineage tracing in epithelial neoplasia Nat. Rev. Cancer 13 2013 161 171 23388619
  2. Barker N. van Es J.H. Kuipers J. Kujala P. van den Born M. Cozijnsen M. Haegebarth A. Korving J. Begthel H. Peters P.J. Clevers H. Identification of stem cells in small intestine and colon by marker gene Lgr5 Nature 449 2007 1003 1007 17934449
  3. Barker N. van Oudenaarden A. Clevers H. Identifying the stem cell of the intestinal crypt: strategies and pitfalls Cell Stem Cell 11 2012 452 460 23040474
  4. Blanpain C. Stem cells: Skin regeneration and repair Nature 464 2010 686 687 20360726
  5. Brownell I. Guevara E. Bai C.B. Loomis C.A. Joyner A.L. Nerve-derived sonic hedgehog defines a niche for hair follicle stem cells capable of becoming epidermal stem cells Cell Stem Cell 8 2011 552 565 21549329 PMC3089905
  6. Caulin C. Nguyen T. Lang G.A. Goepfert T.M. Brinkley B.R. Cai W.W. Lozano G. Roop D.R. An inducible mouse model for skin cancer reveals distinct roles for gain- and loss-of-function p53 mutations J. Clin. Invest. 117 2007 1893 1901 17607363 PMC1904325
  7. Choi N. Zhang B. Zhang L. Ittmann M. Xin L. Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation Cancer Cell 21 2012 253 265 22340597 PMC3285423
  8. Cottle D.L. Kretzschmar K. Schweiger P.J. Quist S.R. Gollnick H.P. Natsuga K. Aoyagi S. Watt F.M. c-MYC-induced sebaceous gland differentiation is controlled by an androgen receptor/p53 axis Cell Rep 3 2013 427 441 23403291 PMC3778892
  9. Du P. Kibbe W.A. Lin S.M. lumi: a pipeline for processing Illumina microarray Bioinformatics 24 2008 1547 1548 18467348
  10. Frances D. Niemann C. Stem cell dynamics in sebaceous gland morphogenesis in mouse skin Dev. Biol. 363 2012 138 146 22227295
  11. Ghazizadeh S. Taichman L.B. Multiple classes of stem cells in cutaneous epithelium: a lineage analysis of adult mouse skin EMBO J. 20 2001 1215 1222 11250888 PMC145528
  12. Gur G. Rubin C. Katz M. Amit I. Citri A. Nilsson J. Amariglio N. Henriksson R. Rechavi G. Hedman H. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation EMBO J. 23 2004 3270 3281 15282549 PMC514515
  13. Horsley V. O’Carroll D. Tooze R. Ohinata Y. Saitou M. Obukhanych T. Nussenzweig M. Tarakhovsky A. Fuchs E. Blimp1 defines a progenitor population that governs cellular input to the sebaceous gland Cell 126 2006 597 609 16901790 PMC2424190
  14. Huang W. Sherman B.T. Lempicki R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources Nat. Protoc. 4 2009 44 57 19131956
  15. Ito M. Liu Y. Yang Z. Nguyen J. Liang F. Morris R.J. Cotsarelis G. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis Nat. Med. 11 2005 1351 1354 16288281
  16. Jaks V. Barker N. Kasper M. van Es J.H. Snippert H.J. Clevers H. Toftgård R. Lgr5 marks cycling, yet long-lived, hair follicle stem cells Nat. Genet. 40 2008 1291 1299 18849992
  17. Jaks V. Kasper M. Toftgård R. The hair follicle-a stem cell zoo Exp. Cell Res. 316 2010 1422 1428 20338163
  18. Jensen U.B. Yan X. Triel C. Woo S.H. Christensen R. Owens D.M. A distinct population of clonogenic and multipotent murine follicular keratinocytes residing in the upper isthmus J. Cell Sci. 121 2008 609 617 18252795 PMC2963074
  19. Jensen K.B. Collins C.A. Nascimento E. Tan D.W. Frye M. Itami S. Watt F.M. Lrig1 expression defines a distinct multipotent stem cell population in mammalian epidermis Cell Stem Cell 4 2009 427 439 19427292 PMC2698066
  20. Jensen K.B. Driskell R.R. Watt F.M. Assaying proliferation and differentiation capacity of stem cells using disaggregated adult mouse epidermis Nat. Protoc. 5 2010 898 911 20431535
  21. Kasper M. Jaks V. Are A. Bergström A. Schwäger A. Svärd J. Teglund S. Barker N. Toftgård R. Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes Proc. Natl. Acad. Sci. USA 108 2011 4099 4104 21321199 PMC3054016
  22. Laederich M.B. Funes-Duran M. Yen L. Ingalla E. Wu X. Carraway K.L. 3rd Sweeney C. The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases J. Biol. Chem. 279 2004 47050 47056 15345710
  23. Langton A.K. Herrick S.E. Headon D.J. An extended epidermal response heals cutaneous wounds in the absence of a hair follicle stem cell contribution J. Invest. Dermatol. 128 2008 1311 1318 18037901
  24. Lapouge G. Youssef K.K. Vokaer B. Achouri Y. Michaux C. Sotiropoulou P.A. Blanpain C. Identifying the cellular origin of squamous skin tumors Proc. Natl. Acad. Sci. USA 108 2011 7431 7436 21502497 PMC3088632
  25. Levy V. Lindon C. Harfe B.D. Morgan B.A. Distinct stem cell populations regenerate the follicle and interfollicular epidermis Dev. Cell 9 2005 855 861 16326396
  26. Levy V. Lindon C. Zheng Y. Harfe B.D. Morgan B.A. Epidermal stem cells arise from the hair follicle after wounding FASEB J. 21 2007 1358 1366 17255473
  27. Lu L. Teixeira V.H. Yuan Z. Graham T.A. Endesfelder D. Kolluri K. Al-Juffali N. Hamilton N. Nicholson A.G. Falzon M. LRIG1 regulates cadherin-dependent contact inhibition directing epithelial homeostasis and pre-invasive squamous cell carcinoma development J. Pathol. 229 2013 608 620 23208928 PMC3806036
  28. Madisen L. Zwingman T.A. Sunkin S.M. Oh S.W. Zariwala H.A. Gu H. Ng L.L. Palmiter R.D. Hawrylycz M.J. Jones A.R. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain Nat. Neurosci. 13 2010 133 140 20023653 PMC2840225
  29. Mascré G. Dekoninck S. Drogat B. Youssef K.K. Broheé S. Sotiropoulou P.A. Simons B.D. Blanpain C. Distinct contribution of stem and progenitor cells to epidermal maintenance Nature 489 2012 257 262 22940863
  30. Means A.L. Xu Y. Zhao A. Ray K.C. Gu G. A CK19(CreERT) knockin mouse line allows for conditional DNA recombination in epithelial cells in multiple endodermal organs Genesis 46 2008 318 323 18543299 PMC3735352
  31. Morris R.J. Liu Y. Marles L. Yang Z. Trempus C. Li S. Lin J.S. Sawicki J.A. Cotsarelis G. Capturing and profiling adult hair follicle stem cells Nat. Biotechnol. 22 2004 411 417 15024388
  32. Mootha V.K. Lindgren C.M. Eriksson K.F. Subramanian A. Sihag S. Lehar J. Puigserver P. Carlsson E. Ridderstråle M. Laurila E. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes Nat. Genet. 34 2003 267 273 12808457
  33. Nagao K. Kobayashi T. Moro K. Ohyama M. Adachi T. Kitashima D.Y. Ueha S. Horiuchi K. Tanizaki H. Kabashima K. Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin Nat. Immunol. 13 2012 744 752 22729248 PMC4115277
  34. Nijhof J.G. Braun K.M. Giangreco A. van Pelt C. Kawamoto H. Boyd R.L. Willemze R. Mullenders L.H. Watt F.M. de Gruijl F.R. van Ewijk W. The cell-surface marker MTS24 identifies a novel population of follicular keratinocytes with characteristics of progenitor cells Development 133 2006 3027 3037 16818453
  35. Nowak J.A. Polak L. Pasolli H.A. Fuchs E. Hair follicle stem cells are specified and function in early skin morphogenesis Cell Stem Cell 3 2008 33 43 18593557 PMC2877596
  36. Ousset M. Van Keymeulen A. Bouvencourt G. Sharma N. Achouri Y. Simons B.D. Blanpain C. Multipotent and unipotent progenitors contribute to prostate postnatal development Nat. Cell Biol. 14 2012 1131 1138 23064263
  37. Owens D.M. Watt F.M. Contribution of stem cells and differentiated cells to epidermal tumours Nat. Rev. Cancer 3 2003 444 451 12778134
  38. Petersson M. Brylka H. Kraus A. John S. Rappl G. Schettina P. Niemann C. TCF/Lef1 activity controls establishment of diverse stem and progenitor cell compartments in mouse epidermis EMBO J. 30 2011 3004 3018 21694721 PMC3160179
  39. Plikus M.V. Gay D.L. Treffeisen E. Wang A. Supapannachart R.J. Cotsarelis G. Epithelial stem cells and implications for wound repair Semin. Cell Dev. Biol. 23 2012 946 953 23085626 PMC3518754
  40. Rock J.R. Hogan B.L. Epithelial progenitor cells in lung development, maintenance, repair, and disease Annu. Rev. Cell Dev. Biol. 27 2011 493 512 21639799
  41. Snippert H.J. Haegebarth A. Kasper M. Jaks V. van Es J.H. Barker N. van de Wetering M. van den Born M. Begthel H. Vries R.G. Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin Science 327 2010 1385 1389 20223988
  42. van der Weyden L. Alcolea M.P. Jones P.H. Rust A.G. Arends M.J. Adams D.J. Acute sensitivity of the oral mucosa to oncogenic K-ras J. Pathol. 224 2011 22 32 21381032 PMC3627303
  43. Van Keymeulen A. Blanpain C. Tracing epithelial stem cells during development, homeostasis, and repair J. Cell Biol. 197 2012 575 584 22641343 PMC3365500
  44. White A.C. Tran K. Khuu J. Dang C. Cui Y. Binder S.W. Lowry W.E. Defining the origins of Ras/p53-mediated squamous cell carcinoma Proc. Natl. Acad. Sci. USA 108 2011 7425 7430 21502519 PMC3088581
  45. Wong S.Y. Reiter J.F. Wounding mobilizes hair follicle stem cells to form tumors Proc. Natl. Acad. Sci. USA 108 2011 4093 4098 21321207 PMC3053984
  46. Wong V.W. Stange D.E. Page M.E. Buczacki S. Wabik A. Itami S. van de Wetering M. Poulsom R. Wright N.A. Trotter M.W. Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling Nat. Cell Biol. 14 2012 401 408 22388892 PMC3378643
  47. Youssef K.K. Van Keymeulen A. Lapouge G. Beck B. Michaux C. Achouri Y. Sotiropoulou P.A. Blanpain C. Identification of the cell lineage at the origin of basal cell carcinoma Nat. Cell Biol. 12 2010 299 305 20154679

Authors
Page, M. E., Lombard, P., Ng, F., Göttgens, B., & Jensen, K. B.
Affiliations
  • Wellcome/MRC Cambridge Stem Cell Institute (GB)
  • University of Copenhagen (DK)
Corresponding author
Jensen, Kim B.
ORCID
Venue
Cell Stem Cell
Publisher
Elsevier BV
Published
2013-10
Volume
13
Issue
4
Pages
471-482
ISSN
  • 1875-9777 (ISSN-L)
  • 1934-5909
DOI
10.1016/j.stem.2013.07.010
PMC
PMC3793873
OpenAlex
W2102296842
Cited by
320
References
51
Citations by year
2026: 11 · 2025: 16 · 2024: 33 · 2023: 15 · 2022: 21 · 2021: 30 · 2020: 31 · 2019: 27 · 2018: 37 · 2017: 23 · 2016: 31 · 2015: 26 · 2014: 16 · 2013: 3
FWCI
30.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell stem cell (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders
  • Sundhed og Sygdom, Det Frie Forskningsråd
  • Wellcome Trust (079249, 100140, WT088454MA)
  • Cancer Research UK (12765)
  • National Centre for the Replacement, Refinement and Reduction of Animals in Research (G0900729/1)
  • Lundbeckfonden (R105-2011-9755)
  • Medical Research Council (MC_PC_12009)
  • Biotechnology and Biological Sciences Research Council (BB/I00050X/1)
Topics
  • Health Sciences › Medicine › Urology › Hair Growth and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
epidermal stem cells, Lrig1, pilosebaceous unit, sebaceous glands, infundibulum, hair follicle, interfollicular epidermis, compartmentalization, wound healing, lineage plasticity, oncogene activation, epidermal hyperplasia, skin tumor initiation
MeSH terms
Epidermal Cells, Animals, Epidermis, Membrane Glycoproteins, Mice, Inbred C57BL, Nerve Tissue Proteins, Stem Cells, Keratinocytes, Oligonucleotide Array Sequence Analysis, Cell Proliferation, Mice

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