Skip to main content

Dedifferentiation and Skin Regeneration

  • Chapter
  • First Online:
Cellular Dedifferentiation and Regenerative Medicine

Abstract

Skin homeostasis maintenance, skin repair, and regeneration are the hot topics in multiple disciplines, ranging from dermatology, plastic surgery, trauma, and cutaneous wound healing. Epidermal stem cells are thought to be the primary cell reservoir for skin repair and restoration. And it is generally known that skin cell would renew itself every 2–4 weeks. However, owing to the difficulty in isolation, sampling, and limited quantities of epidermal stem cells, epidermal cell dedifferentiation renders novel opportunities for clinical practice of skin repair and regeneration. In patients with profound burns, the wound can get into the muscle tissues and impair sweat glands. Keratinocyte regeneration without skin appendage restoring would deteriorate patients’ prognosis, as sweat glands play significant parts in body temperature regulation and homeostasis maintenance. The likelihood may be offered by mesenchymal stem cells’ plasticity to regenerate sweat glands after severe burn. In particular, recent researches have altered the possibility to reality. This review collected research milestones in this field, and some fundamental achievements were completed by many contributors of this book. For some heritage dermatological disorders, researches have reported that patient-specific iPSCs from keratinocytes could achieve good clinical outcomes. Besides, melanocyte development, pigmentation, and dedifferentiation are also illustrated in this review, which has opened a new avenue for obtaining precursor cells.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Fu X, Sun X, Li X, Sheng Z. Dedifferentiation of epidermal cells to stem cells in vivo. Lancet. 2001;358(9287):1067–8.

    Article  CAS  PubMed  Google Scholar 

  2. Sun X, Fu X, Han W, Zhao Y, Liu H, Sheng Z. Dedifferentiation of human terminally differentiating keratinocytes into their precursor cells induced by basic fibroblast growth factor. Biol Pharm Bull. 2011;34(7):1037–45.

    Article  CAS  PubMed  Google Scholar 

  3. Yang Y, Xia T, Chen F, Wei W, Liu C, He S, Li X. Electrospun fibers with plasmid bFGF polyplex loadings promote skin wound healing in diabetic rats. Mol Pharm. 2012;9(1):48–58.

    Article  PubMed  Google Scholar 

  4. Cai S, Pan Y, Fu XB, Lei YH, Sun TZ, Wang J, Sheng ZY. Dedifferentiation of human epidermal keratinocytes induced by UV in vitro. J Health Sci. 2009;55(5):709–19.

    Article  CAS  Google Scholar 

  5. Li H, Fu X, Zhang L, Sun T, Wang J. In vivo dedifferentiation of human epidermal cells. Cell Biol Int. 2007;31(11):1436–41.

    Article  CAS  PubMed  Google Scholar 

  6. Mannik J, Alzayady K, Ghazizadeh S. Regeneration of multilineage skin epithelia by differentiated keratinocytes. J Invest Dermatol. 2010;130(2):388–97.

    Article  CAS  PubMed  Google Scholar 

  7. Zhang C, Fu X, Chen P, Bao X, Li F, Sun X, Lei Y, Cai S, Sun T, Sheng Z. Dedifferentiation derived cells exhibit phenotypic and functional characteristics of epidermal stem cells. J Cell Mol Med. 2010;14(5):1135–45.

    CAS  PubMed  Google Scholar 

  8. Zhang C, Chen P, Fei Y, Liu B, Ma K, Fu X, Zhao Z, Sun T, Sheng Z. Wnt/beta-catenin signaling is critical for dedifferentiation of aged epidermal cells in vivo and in vitro. Aging Cell. 2012;11(1):14–23.

    Article  CAS  PubMed  Google Scholar 

  9. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434(7035):843–50.

    Article  CAS  PubMed  Google Scholar 

  10. Choi YS, Zhang Y, Xu M, Yang Y, Ito M, Peng T, Cui Z, Nagy A, Hadjantonakis AK, Lang RA, Cotsarelis G, Andl T, Morrisey EE, Millar SE. Distinct functions for Wnt/beta-catenin in hair follicle stem cell proliferation and survival and interfollicular epidermal homeostasis. Cell Stem Cell. 2013;13(6):720–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fathke C, Wilson L, Shah K, Kim B, Hocking A, Moon R, Isik F. Wnt signaling induces epithelial differentiation during cutaneous wound healing. BMC Cell Biol. 2006;7:4.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Dumesic PA, Scholl FA, Barragan DI, Khavari PA. Erk1/2 MAP kinases are required for epidermal G2/M progression. J Cell Biol. 2009;185(3):409–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yamamoto H, Ochiya T, Takeshita F, Toriyama-Baba H, Hirai K, Sasaki H, Sasaki H, Sakamoto H, Yoshida T, Saito I, Terada M. Enhanced skin carcinogenesis in cyclin D1-conditional transgenic mice: cyclin D1 alters keratinocyte response to calcium-induced terminal differentiation. Cancer Res. 2002;62(6):1641–7.

    CAS  PubMed  Google Scholar 

  14. Li JF, Duan HF, Wu CT, Zhang DJ, Deng Y, Yin HL, Han B, Gong HC, Wang HW, Wang YL. HGF accelerates wound healing by promoting the dedifferentiation of epidermal cells through beta1-integrin/ILK pathway. Biomed Res Int. 2013;2013:470418.

    PubMed  Google Scholar 

  15. Hannigan GE, Leung-Hagesteijn C, Fitz-Gibbon L, Coppolino MG, Radeva G, Filmus J, Bell JC, Dedhar S. Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase. Nature. 1996;379(6560):91–6.

    Article  CAS  PubMed  Google Scholar 

  16. Jones PH, Harper S, Watt FM. Stem cell patterning and fate in human epidermis. Cell. 1995;80(1):83–93.

    Article  CAS  PubMed  Google Scholar 

  17. Serrano I, Diez-Marques ML, Rodriguez-Puyol M, Herrero-Fresneda I, Raimundo Garcia dM, Dedhar S, Ruiz-Torres MP, Rodriguez-Puyol D. Integrin-linked kinase (ILK) modulates wound healing through regulation of hepatocyte growth factor (HGF). Exp Cell Res. 2012;318(19):2470–81.

    Article  CAS  PubMed  Google Scholar 

  18. Xie W, Li F, Kudlow JE, Wu C. Expression of the integrin-linked kinase (ILK) in mouse skin: loss of expression in suprabasal layers of the epidermis and up-regulation by erbB-2. Am J Pathol. 1998;153(2):367–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Harrisingh MC, Perez-Nadales E, Parkinson DB, Malcolm DS, Mudge AW, Lloyd AC. The Ras/Raf/ERK signalling pathway drives Schwann cell dedifferentiation. EMBO J. 2004;23(15):3061–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yoon YM, Kim SJ, Oh CD, Ju JW, Song WK, Yoo YJ, Huh TL, Chun JS. Maintenance of differentiated phenotype of articular chondrocytes by protein kinase C and extracellular signal-regulated protein kinase. J Biol Chem. 2002;277(10):8412–20.

    Article  CAS  PubMed  Google Scholar 

  21. Vogel S, Kubin T, von der Ahe D, Deindl E, Schaper W, Zimmermann R. MEK hyperphosphorylation coincides with cell cycle shut down of cultured smooth muscle cells. J Cell Physiol. 2006;206(1):25–34.

    Article  CAS  PubMed  Google Scholar 

  22. Grinnell KL, Yang B, Eckert RL, Bickenbach JR. De-differentiation of mouse interfollicular keratinocytes by the embryonic transcription factor Oct-4. J Invest Dermatol. 2007;127(2):372–80.

    Article  CAS  PubMed  Google Scholar 

  23. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.

    Article  CAS  PubMed  Google Scholar 

  24. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.

    Article  CAS  PubMed  Google Scholar 

  25. Aasen T, Raya A, Barrero MJ, Garreta E, Consiglio A, Gonzalez F, Vassena R, Bilic J, Pekarik V, Tiscornia G, Edel M, Boue S, Izpisua Belmonte JC. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol. 2008;26(11):1276–84.

    Article  CAS  PubMed  Google Scholar 

  26. Maherali N, Ahfeldt T, Rigamonti A, Utikal J, Cowan C, Hochedlinger K. A high-efficiency system for the generation and study of human induced pluripotent stem cells. Cell Stem Cell. 2008;3(3):340–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Novak A, Shtrichman R, Germanguz I, Segev H, Zeevi-Levin N, Fishman B, Mandel YE, Barad L, Domev H, Kotton D, Mostoslavsky G, Binah O, Itskovitz-Eldor J. Enhanced reprogramming and cardiac differentiation of human keratinocytes derived from plucked hair follicles, using a single excisable lentivirus. Cell Reprogram. 2010;12(6):665–78.

    Article  CAS  PubMed  Google Scholar 

  28. Kim JB, Zaehres H, Wu G, Gentile L, Ko K, Sebastiano V, Arauzo-Bravo MJ, Ruau D, Han DW, Zenke M, Scholer HR. Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature. 2008;454(7204):646–50.

    Article  CAS  PubMed  Google Scholar 

  29. Eminli S, Utikal J, Arnold K, Jaenisch R, Hochedlinger K. Reprogramming of neural progenitor cells into induced pluripotent stem cells in the absence of exogenous Sox2 expression. Stem Cells. 2008;26(10):2467–74.

    Article  CAS  PubMed  Google Scholar 

  30. Aoi T, Yae K, Nakagawa M, Ichisaka T, Okita K, Takahashi K, Chiba T, Yamanaka S. Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science. 2008;321(5889):699–702.

    Article  CAS  PubMed  Google Scholar 

  31. Ohmine S, Squillace KA, Hartjes KA, Deeds MC, Armstrong AS, Thatava T, Sakuma T, Terzic A, Kudva Y, Ikeda Y. Reprogrammed keratinocytes from elderly type 2 diabetes patients suppress senescence genes to acquire induced pluripotency. Aging (Albany NY). 2012;4(1):60–73.

    Article  CAS  Google Scholar 

  32. Almaani N, Nagy N, Liu L, Dopping-Hepenstal PJ, Lai-Cheong JE, Clements SE, Techanukul T, Tanaka A, Mellerio JE, McGrath JA. Revertant mosaicism in recessive dystrophic epidermolysis bullosa. J Invest Dermatol. 2010;130(7):1937–40.

    Article  CAS  PubMed  Google Scholar 

  33. Tolar J, McGrath JA, Xia L, Riddle MJ, Lees CJ, Eide C, Keene DR, Liu L, Osborn MJ, Lund TC, Blazar BR, Wagner JE. Patient-specific naturally gene-reverted induced pluripotent stem cells in recessive dystrophic epidermolysis bullosa. J Invest Dermatol. 2014;134(5):1246–54.

    Article  CAS  PubMed  Google Scholar 

  34. Umegaki-Arao N, Pasmooij AM, Itoh M, Cerise JE, Guo Z, Levy B, Gostynski A, Rothman LR, Jonkman MF, Christiano AM. Induced pluripotent stem cells from human revertant keratinocytes for the treatment of epidermolysis bullosa. Sci Transl Med. 2014;6(264):264ra164.

    Article  PubMed  Google Scholar 

  35. Zhao Z, Jin C, Ding K, Ge X, Dai L. Dedifferentiation of human epidermal melanocytes into melanoblasts in vitro. Exp Dermatol. 2012;21(7):504–8.

    Article  CAS  PubMed  Google Scholar 

  36. Dupin E, Glavieux C, Vaigot P, Le Douarin NM. Endothelin 3 induces the reversion of melanocytes to glia through a neural crest-derived glial-melanocytic progenitor. Proc Natl Acad Sci U S A. 2000;97(14):7882–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dupin E, Real C, Glavieux-Pardanaud C, Vaigot P, Le Douarin NM. Reversal of developmental restrictions in neural crest lineages: transition from Schwann cells to glial-melanocytic precursors in vitro. Proc Natl Acad Sci U S A. 2003;100(9):5229–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Real C, Glavieux-Pardanaud C, Le Douarin NM, Dupin E. Clonally cultured differentiated pigment cells can dedifferentiate and generate multipotent progenitors with self-renewing potential. Dev Biol. 2006;300(2):656–69.

    Article  CAS  PubMed  Google Scholar 

  39. Kormos B, Belso N, Bebes A, Szabad G, Bacsa S, Szell M, Kemeny L, Bata-Csorgo Z. In vitro dedifferentiation of melanocytes from adult epidermis. PLoS One. 2011;6(2):e17197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zabierowski SE, Baubet V, Himes B, Li L, Fukunaga-Kalabis M, Patel S, McDaid R, Guerra M, Gimotty P, Dahmane N, Herlyn M. Direct reprogramming of melanocytes to neural crest stem-like cells by one defined factor. Stem Cells. 2011;29(11):1752–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Utikal J, Maherali N, Kulalert W, Hochedlinger K. Sox2 is dispensable for the reprogramming of melanocytes and melanoma cells into induced pluripotent stem cells. J Cell Sci. 2009;122(Pt 19):3502–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer-Verlag GmbH Germany

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Fu, X., Zhao, A., Hu, T. (2018). Dedifferentiation and Skin Regeneration. In: Cellular Dedifferentiation and Regenerative Medicine. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-56179-9_6

Download citation

  • DOI: https://doi.org/10.1007/978-3-662-56179-9_6

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-56177-5

  • Online ISBN: 978-3-662-56179-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics