Stem cells in nail unit of mammalians

Home/2016, Vol. 4, No. 1/Stem cells in nail unit of mammalians

Cell and Organ Transplantology. 2016; 4(1):138-143.
DOI: 10.22494/COT.V4I1.1

Stem cells in nail unit of mammalians

Kalmukova O. O.
State Institute of Genetic and Regenerative Medicine NAMS of Ukraine, Kyiv, Ukraine
Educational and Scientific Centre “Institute of Biology”, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine

The review analyzes the current state of experimental studies on the ability to obtain and cultivate stem cells from the nail organ and their possible involvement in the regeneration of a limb. It has been known that the nail unit consists of a pool of undifferentiated cells which provide sustained growth and nail repair throughout life. But, nowadays the issue of stem cell niche localization in the nail organ remains unresolved. Also, researchers demonstrated involvement of these cells in the restoration of amputated limbs, in particular, through activation of certain signaling pathways (Wnt, BMP, Notch), and epithelial-mesenchymal interactions, but the detailed mechanism of this process is poorly understood. It is supposed that the nail organ has two sources of undifferentiated cells of different origin: the proximal nail fold and the dorsal part of the nail matrix (K15+, K19+, PHLDA1+); and onychodermis (CD10+, CD34-). However, these markers are not generally accepted, so the search for markers combinations for exhaustive and complete characterization of stem cells from the nail organ continues.

Key words: nail unit, stem cells, onychodermis, limb regeneration

Full Text PDF

1. Saito M, Ohyama M, Amagai M. Exploring the biology of the nail: An intriguing but less-investigated skin appendage. J Dermatol Sci. 2015. Available:
2. De Berker D, Angus B. Proliferative compartments in the normal nail unit. Br J Dermatol. 1996; 135: 555-59.
3. Myung P, Ito M. Dissecting the bulge in hair regeneration. J Clin Invest. 2012; 122: 448-54.
PMid:22293183 PMCid:PMC3266778
4. Naveau A, Seidel K, Klein OD. Tooth, hair and claw: comparing epithelial stem cell niches of ectodermal appendages. Exp Cell Res. 2014; 325(2): 96-103.
PMid:24530577 PMCid:PMC4072742
5. Iannella G, Greco A, Didona D, et al. Vitiligo: Pathogenesis, clinical variants and treatment approaches Autoimmun Rev. 2015. Available:
6. Wcisło-Dziadecka D, Zbiciak-Nylec M, Brzezińska-Wcisło L, et al. TNF-α in a molecularly targeted therap of psoriasis and psoriatic arthritis. Postgrad Med J. 2015. Available: doi:10.1136/postgradmedj-2015-133419.
7. Tucker JrJ. Nail Deformities and Injuries Prim Care Clin Office Pract. 2015. Available:
8. Baran R, Dawber RP, Haneke E. Hair and nail relationship. Skinmed. 2005; 4: 18-23.
10. De Berker DAR, Baran R. Baran & Dawber’s diseases of the nails and their management. 4th ed, Oxford, England: Wiley-Blackwell, 2012. 832 p.
11. LeGros CWE. The problem of the claw in primates. Proc Zool Soc. 1936; 1:1-24.
12. Fleckman P, Karin J, Silva KA, et al. Comparative Anatomy of Mouse and Human Nail Units. Anat Rec (Hoboken). 2013; 296(3): 521-32.
PMid:23408541 PMCid:PMC3579226
13. Perrin C, Langbein L, Schweizer J. Expression of hair keratins in the adult nail unit: an immunohistochemical analysis of the onychogenesis in the proximal nail fold, matrix and nail bed. British Journal of Dermatology. 2004; 151: 362-71.
14. Zaias N. Embryology of the human nail. Arch Dermatol. 1963; 87: 37-53.
15. Saito M, Tucker DK, Kohlhorst D, et al. Classical and desmosomal cadherins at a glance. J Cell Sci. 2012; 125: 2547-52.
PMid:22833291 PMCid:PMC3403229
16. Blaydon DC, Ishii Y, O’Toole EA, et al. The gene encoding R-spondin 4 (RSPO4), a secreted protein implicated in Wnt signaling, is mutated in inherited anonychia. Nat Genet. 2006; 38: 1245-47.
17. Bergmann C, Senderek J, Anhuf D, et al. Mutations in the gene encoding the Wnt-signaling component R-spondin 4 (RSPO4) cause autosomal recessive anonychia. Am J Hum Genet. 2006; 79: 1105-9.
PMid:17186469 PMCid:PMC1698700
18. Aoki M, Kiyonari H, Nakamura H, et al. R-spondin2 expression in the apical ectodermal ridge is essential for outgrowth and patterning in mouse limb development . Dev Growth Differ. 2008; 50: 85-95.
19. Wilson NJ, Hansen CD, Azkur D, et al. Recessive mutations in the gene encoding frizzled 6 cause twenty nail dystrophy— expanding the differential diagnosis for pachyonychia congenita. J Dermatol Sci. 2013; 70: 58-60.
20. Naz G, Pasternack SM, Perrin C, et al. FZD6 encoding the Wnt receptor frizzled 6 is mutated in autosomal-recessive nail dysplasia. Br J Dermatol. 2012; 166: 1088-94.
21. Takeo M, Chou WC, Sun Q, et al. Wnt activation in nail epithelium couples nail growth to digit regeneration . Nature. 2013; 499: 228-32.
PMid:23760480 PMCid:PMC3936678
22. Nakamura M, Ishikawa O. The localization of label-retaining cells in mouse nails. J Invest Dermatol. 2008; 128: 728-30.
23. Yokoyama H, Ogino H, Stoick-Cooper CL, et al. Wnt/β-catenin signaling has an essential role in the initiation of limb regeneration. Dev Biol. 2007; 306(1): 170-78.
PMid:17442299 PMCid:PMC2703180
24. Cai J, Ma L. Msx2 and Foxn1 regulate nail homeostasis Genesis. 2011; 49: 449-59.
PMid:21387539 PMCid:PMC3115482
25. Lin MH, Kopan R. Long-range, nonautonomous effects of activated Notch1 on tissue homeostasis in the nail. Dev Biol. 2003; 263: 343-59.
26. Lee DY, Park JH, Shin HT, et al. The presence and localization of onychodermis (specialized nail mesenchyme) containing onychofibroblasts in the nail unit: a morphological and immunohistochemical study Histopathology. 2012. Available: DOI: 10.1111/j.1365-2559.2012.04210.x.
27. Sellheyer K, Nelson P. The concept of the onychodermis (specialized nail mesenchyme): an embryological assessment and a comparative analysis with the hair follicle. J Cutan Pathol. 2013; 40: 463-71.
28. Park JH, Kim JH, Lee JH, et al. Onychodermis (specialized nail mesenchyme) is present in ectopic nails J Cutan Pathol. 2013; 40: 600-02.
29. Okazaki M, Yoshimura K, Fujiwara H, et al. Induction of hard keratin expression in non-nail-matrical keratinocytes by nail-matrical fibroblasts through epithelial–mesenchymal interactions. Plast Reconstr Surg. 2003; 111: 286-90.
30. Ohyama M, Terunuma A, Tock CL, et al. Characterization and isolation of stem cell-enriched human hair follicle bulge cells. J Clin Invest. 2006; 116: 249-60.
PMid:16395407 PMCid:PMC1323261
31. Ohyama M. Hair follicle bulge: a fascinating reservoir of epithelial stem cells. J Dermatol Sci. 2007; 46: 81–9.
32. Sellheyer K. Nail stem cells. JDDG. 2013; 1103: 235-39.
33. Sellheyer K, Nelson P. The ventral proximal nail fold: stem cell niche of the nail and equivalent to the follicular bulge—a study on developing human skin. 2012; 39: 835-43.
34. Leung Y, Kandyba E, Chen YB, et al. Bifunctional ectodermal stem cells around the nail display dual fate homeostasis and adaptive wounding response toward nail regeneration. Proc Natl Acad Sci USA. 2014; 111: 15114-19.
PMid:25277970 PMCid:PMC4210315
35. Kitahara T, Ogawa H. Cultured nail keratinocytes express hard keratins characteristic of nail and hair in vivo. Arch.Dermatol. Res. 1992; 284: 253-56.
36. Picardo M, Marchese C, Zompetta C, et al. Characterization of human nail matrix cells in vitro [Abstract]. J Invest Dermatol. 1992; 98: 523A.
37. Picardo M, Tosti A, Marchese C, et al. Characterization of cultured nail matrix cells . Journal of the American Academy of Dermatology. 1994; 30(3): 434-40.
38. Kitahara T, Ogawa H. Coexpression of keratins characteristic of skin and hair differentiation in nail cells. J. Invest. Dermatol. 1993; 100: 171-75.
39. Kitahara T, Ogawa H. Variation of differentiation in nail and bovine hoof cells. J. Invest. Dermatol. 1994; 102: 725-29.
40. Kitahara T, Ogawa H. Cellular Features of Differentiation in the Nail. Microscopy research and technique. 1997; 38: 436-42.<436::AID-JEMT11>3.0.CO;2-K
41. Lehoczky JA, Tabin CJ. Lgr6 marks nail stem cells and is required for digit tip regeneration. PNAS. 2015; 112(43): 13249-254.
PMid:26460010 PMCid:PMC4629333
42. Borgens RB. Mice Regrow the Tips of Their Foretoes. Borgens Sciense. 1982; 217: 747-50.
43. Zhao W, Neufeld DA. Bone regrowth in young mice stimulated by nail organ. Exp Zoolog. 1995; 271: 155-59.
44. Rinkevich Y, Lindau P, Ueno H, et al. Germ and lineage restricted stem/progenitors regenerate the mouse digit tip. Nature. 2013; 476(7361): 409-13.
PMid:21866153 PMCid:PMC3812235
45. Mohammad KS, Day FA, Neufeld DA. Bone growth is induced by nail transplantation in amputated proximal phalanges. Calcif Tissue Int. 1999; 65: 408-10.
46. Lehoczky JA, Robert B, Tabin CJ. Mouse digit tip regeneration is mediated by fate-restricted progenitor cells. PNAS. 2011; 108(51): 20609-614.
PMid:22143790 PMCid:PMC3251149
47. Fernando WA, Leininger E, Simkin J, et a1. Wound healing and blastema formation in regenerating digit tips of adult mice. Dev Biol. 2011; 350(2): 301-10.
PMid:21145316 PMCid:PMC3031655
48. Han M, Yang X, Lee J, et al. Development and regeneration of the neonatal digit tip in mice. Dev Biol. 2008; 315: 125-35.
PMid:18234177 PMCid:PMC2329911
49. Tamura K, Ohgo S, Yokoyama HA. Limb blastema cell: A stem cell for morphological Regeneration. Develop. Growth Differ. 2010; 52: 89-99.
50. Yu L, Han M, Yan M, et al. BMP signaling induces digit regeneration in neonatal mice Development. 2010; 137: 551-9.
PMid:20110320 PMCid:PMC2827613
51. Rinkevich Y, Montorob DT, Muhonenb E, et al. Clonal analysis reveals nerve-dependent and independent roles on mammalian hind limb tissue maintenance and regeneration. PNAS. 2014; 111(27): 9846-51.
PMid:24958860 PMCid:PMC4103362
52. Rinkevich Y, Maan ZN, Walmsley GG, et al. Injuries to appendage extremities and digit tips: a clinical and cellular update Developmental Dynamics. 2015. Available: DOI 10.1002/dvdy.24265.
53. Lin GL, Hankenson KD. Integration of BMP, Wnt, and Notch signaling pathways in osteoblast differentiation. J Cell Biochem. 2011; 112(12): 3491-501.
PMid:21793042 PMCid:PMC3202082

Kalmukova OO. Stem cells in nail unit of mammalians. Cell and Organ Transplantology. 2016; 4(1):138-143. doi: 10.22494/COT.V4I1.1


Creative Commons License
Is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.