Ann Dermatol.  2017 Dec;29(6):667-687. 10.5021/ad.2017.29.6.667.

Current and Future Perspectives of Stem Cell Therapy in Dermatology

• Prodinger
• Reichelt J
• Bauer JW
• Laimer M

• KMID: 2395174
• DOI: http://doi.org/10.5021/ad.2017.29.6.667

Abstract

Stem cells are undifferentiated cells capable of generating, sustaining, and replacing terminally differentiated cells and tissues. They can be isolated from embryonic as well as almost all adult tissues including skin, but are also generated through genetic reprogramming of differentiated cells. Preclinical and clinical research has recently tremendously improved stem cell therapy, being a promising treatment option for various diseases in which current medical therapies fail to cure, prevent progression or relieve symptoms. With the main goal of regeneration or sustained genetic correction of damaged tissue, advanced tissue-engineering techniques are especially applicable for many dermatological diseases including wound healing, genodermatoses (like the severe blistering disorder epidermolysis bullosa) and chronic (auto-)inflammatory diseases. This review summarizes general aspects as well as current and future perspectives of stem cell therapy in dermatology.

Keyword

Epidermal stem cells; Epidermolysis bullosa; Induced pluripotent stem cells; Mesenchymal multipotent stromal cells; Stem cell therapy; Wound healing

MeSH Terms

Adult
Blister
Dermatology*
Epidermolysis Bullosa
Humans
Induced Pluripotent Stem Cells
Regeneration
Skin
Stem Cells*
Wound Healing

Figure

• 

  Fig. 1 Classical hierachial model of stem cell differentiation. ESC: embryonic stem cell, iPSC: induced pluripotent stem cell, NSC: neural stem cell, EpSC: epidermal stem cell, HSC: hematopoietic stem cell, MSC: mesenchymal stem cell.

• 

  Fig. 2 The hierarchical model states that the epidermis is built of discrete epidermal proliferative units with a central slow-cycling stem cell that yields rapidly dividing TACs, which departs from the basal layer after several divisions to generate upward columnar units of differentiating cells. The stochastic model suggests that the epidermal basal layer is composed of a single type of proliferative progenitors whose daughter cells choose randomly to differentiate or remain as progenitors. Each division of basal cells can yield three different outcomes: (1) one differentiated daughter that withdraws from cell cycle and leaves the basal layer, and one progenitor that remains in the basal layer, continue to divide; (2) two differentiated daugthers; and (3) two basal progenitors. Although the fate choices are random, the probabilities of different outcomes are similar, so that the generation of differentiated cells and the maintenance of committed progenitor pools are balanced, guaranteeing long-term homeostasis. Predictions of lineage-tracing results from each model are shown via the red stained cells; cells with prominent red colors are the ones retaining lineage-traced marks30. SC: stem cell, TAC: transit amplyfying cell (rapidly dividing), PC: dividing progenitor cell.

Reference

1. Lanza RP, Atala A. Essentials of stem cell biology. 3rd ed. Amsterdam: Academic Press;2014. p. XXIII-93.

2. Verfaillie CM, Pera MF, Lansdorp PM. Stem cells: hype and reality. Hematology Am Soc Hematol Educ Program. 2002; 369–391.

3. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998; 282:1145–1147.

4. Williams JM, Petersen BE. rigin, evolution, and direction of human somatic cell therapy. In : Olmo DG, García-Verdugo JM, Alemany J, Gutiérrez-Fuente JA, editors. Cell therapy. Madrid: McGraw Hill-Interamericana;2008. p. 3–14.

5. Blanpain C, Lowry WE, Geoghegan A, Polak L, Fuchs E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell. 2004; 118:635–648.

6. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999; 284:143–147.

7. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126:663–676.

8. Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature. 2007; 448:313–317.

9. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007; 318:1917–1920.

10. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007; 131:861–872.

11. Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K. Induced pluripotent stem cells generated without viral integration. Science. 2008; 322:945–949.

12. Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin II, et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science. 2009; 324:797–801.

13. Zhou H, Wu S, Joo JY, Zhu S, Han DW, Lin T, et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell. 2009; 4:381–384.

14. Warren L, Manos PD, Ahfeldt T, Loh YH, Li H, Lau F, et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell. 2010; 7:618–630.

15. Shi Y, Desponts C, Do JT, Hahm HS, Schöler HR, Ding S. Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell. 2008; 3:568–574.

16. Kumar D, Talluri TR, Anand T, Kues WA. Transposon-based reprogramming to induced pluripotency. Histol Histopathol. 2015; 30:1397–1409.

17. Bilousova G, Roop DR. Induced pluripotent stem cells in dermatology: potentials, advances, and limitations. Cold Spring Harb Perspect Med. 2014; 4:a015164.

18. Beaver CM, Ahmed A, Masters JR. Clonogenicity: holoclones and meroclones contain stem cells. PLoS One. 2014; 9:e89834.

19. Gola M, Czajkowski R, Bajek A, Dura A, Drewa T. Melanocyte stem cells: biology and current aspects. Med Sci Monit. 2012; 18:RA155–RA159.

20. Nemeth K, Mezey E. Bone marrow stromal cells as immunomodulators. A primer for dermatologists. J Dermatol Sci. 2015; 77:11–20.

21. Tanabe S. Signaling involved in stem cell reprogramming and differentiation. World J Stem Cells. 2015; 7:992–998.

22. Van Camp JK, Beckers S, Zegers D, Van Hul W. Wnt signaling and the control of human stem cell fate. Stem Cell Rev. 2014; 10:207–229.

23. Ring A, Kim YM, Kahn M. Wnt/catenin signaling in adult stem cell physiology and disease. Stem Cell Rev. 2014; 10:512–525.

24. Blanpain C, Fuchs E. Epidermal stem cells of the skin. Annu Rev Cell Dev Biol. 2006; 22:339–373.

25. Barrandon Y, Green H. Three clonal types of keratinocyte with different capacities for multiplication. Proc Natl Acad Sci U S A. 1987; 84:2302–2306.

26. Claudinot S, Nicolas M, Oshima H, Rochat A, Barrandon Y. Long-term renewal of hair follicles from clonogenic multipotent stem cells. Proc Natl Acad Sci U S A. 2005; 102:14677–14682.

27. Blanpain C, Fuchs E. Epidermal homeostasis: a balancing act of stem cells in the skin. Nat Rev Mol Cell Biol. 2009; 10:207–217.

28. Senoo M. Epidermal stem cells in homeostasis and wound repair of the skin. Adv Wound Care (New Rochelle). 2013; 2:273–282.

29. Rompolas P, Mesa KR, Kawaguchi K, Park S, Gonzalez D, Brown S, et al. Spatiotemporal coordination of stem cell commitment during epidermal homeostasis. Science. 2016; 352:1471–1474.

30. Hsu YC, Li L, Fuchs E. Emerging interactions between skin stem cells and their niches. Nat Med. 2014; 20:847–856.

31. Ovadia J, Nie Q. Stem cell niche structure as an inherent cause of undulating epithelial morphologies. Biophys J. 2013; 104:237–246.

32. Choi HR, Byun SY, Kwon SH, Park KC. Niche interactions in epidermal stem cells. World J Stem Cells. 2015; 7:495–501.

33. Kaur P, Li A. Adhesive properties of human basal epidermal cells: an analysis of keratinocyte stem cells, transit amplifying cells, and postmitotic differentiating cells. J Invest Dermatol. 2000; 114:413–420.

34. Kretzschmar K, Watt FM. Markers of epidermal stem cell subpopulations in adult mammalian skin. Cold Spring Harb Perspect Med. 2014; 4:a013631.

35. Pellegrini G, Dellambra E, Golisano O, Martinelli E, Fantozzi I, Bondanza S, et al. p63 identifies keratinocyte stem cells. Proc Natl Acad Sci U S A. 2001; 98:3156–3161.

36. Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell. 1990; 61:1329–1337.

37. Ito M, Liu Y, Yang Z, Nguyen J, Liang F, Morris RJ, Cotsarelis G. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med. 2005; 11:1351–1354.

38. Clewes O, Narytnyk A, Gillinder KR, Loughney AD, Murdoch AP, Sieber-Blum M. Human epidermal neural crest stem cells (hEPI-NCSC)--characterization and directed differentiation into osteocytes and melanocytes. Stem Cell Rev. 2011; 7:799–814.

39. Ghazizadeh S, Taichman LB. Multiple classes of stem cells in cutaneous epithelium: a lineage analysis of adult mouse skin. EMBO J. 2001; 20:1215–1222.

40. Lang D, Mascarenhas JB, Shea CR. Melanocytes, melanocyte stem cells, and melanoma stem cells. Clin Dermatol. 2013; 31:166–178.

41. Fernandes KJ, McKenzie IA, Mill P, Smith KM, Akhavan M, Barnabé-Heider F, et al. A dermal niche for multipotent adult skin-derived precursor cells. Nat Cell Biol. 2004; 6:1082–1093.

42. Chen S, Takahara M, Kido M, Takeuchi S, Uchi H, Tu Y, et al. Increased expression of an epidermal stem cell marker, cytokeratin 19, in cutaneous squamous cell carcinoma. Br J Dermatol. 2008; 159:952–955.

43. Lin HT, Otsu M, Nakauchi H. Stem cell therapy: an exercise in patience and prudence. Philos Trans R Soc Lond B Biol Sci. 2013; 368:20110334.

44. Mavilio F, Pellegrini G, Ferrari S, Di Nunzio F, Di Iorio E, Recchia A, et al. Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells. Nat Med. 2006; 12:1397–1402.

45. Ronfard V, Rives JM, Neveux Y, Carsin H, Barrandon Y. Long-term regeneration of human epidermis on third degree burns transplanted with autologous cultured epithelium grown on a fibrin matrix. Transplantation. 2000; 70:1588–1598.

46. Pellegrini G, Ranno R, Stracuzzi G, Bondanza S, Guerra L, Zambruno G, et al. The control of epidermal stem cells (holoclones) in the treatment of massive full-thickness burns with autologous keratinocytes cultured on fibrin. Transplantation. 1999; 68:868–879.

47. De Luca M, Pellegrini G, Green H. Regeneration of squamous epithelia from stem cells of cultured grafts. Regen Med. 2006; 1:45–57.

48. Yan XL, Fu CJ, Chen L, Qin JH, Zeng Q, Yuan HF, et al. Mesenchymal stem cells from primary breast cancer tissue promote cancer proliferation and enhance mammosphere formation partially via EGF/EGFR/Akt pathway. Breast Cancer Res Treat. 2012; 132:153–164.

49. Roufosse CA, Direkze NC, Otto WR, Wright NA. Circulating mesenchymal stem cells. Int J Biochem Cell Biol. 2004; 36:585–597.

50. Marfia G, Navone SE, Di Vito C, Ughi N, Tabano S, Miozzo M, et al. Mesenchymal stem cells: potential for therapy and treatment of chronic non-healing skin wounds. Organogenesis. 2015; 11:183–206.

51. Sheng G. The developmental basis of mesenchymal stem/stromal cells (MSCs). BMC Dev Biol. 2015; 15:44.

52. Malgieri A, Kantzari E, Patrizi MP, Gambardella S. Bone marrow and umbilical cord blood human mesenchymal stem cells: state of the art. Int J Clin Exp Med. 2010; 3:248–269.

53. Conget PA, Minguell JJ. Phenotypical and functional properties of human bone marrow mesenchymal progenitor cells. J Cell Physiol. 1999; 181:67–73.

54. Oswald J, Boxberger S, Jørgensen B, Feldmann S, Ehninger G, Bornhäuser M, et al. Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells. 2004; 22:377–384.

55. Burdon TJ, Paul A, Noiseux N, Prakash S, Shum-Tim D. Bone marrow stem cell derived paracrine factors for regenerative medicine: current perspectives and therapeutic potential. Bone Marrow Res. 2011; 2011:207326.

56. Ma S, Xie N, Li W, Yuan B, Shi Y, Wang Y. Immunobiology of mesenchymal stem cells. Cell Death Differ. 2014; 21:216–225.

57. Ma OK, Chan KH. Immunomodulation by mesenchymal stem cells: interplay between mesenchymal stem cells and regulatory lymphocytes. World J Stem Cells. 2016; 8:268–278.

58. Castro-Manrreza ME, Montesinos JJ. Immunoregulation by mesenchymal stem cells: biological aspects and clinical applications. J Immunol Res. 2015; 2015:394917.

59. Shin TH, Kim HS, Choi SW, Kang KS. Mesenchymal stem cell therapy for inflammatory skin diseases: clinical potential and mode of action. Int J Mol Sci. 2017; 18:E244.

60. Farini A, Sitzia C, Erratico S, Meregalli M, Torrente Y. Clinical applications of mesenchymal stem cells in chronic diseases. Stem Cells Int. 2014; 2014:306573.

61. Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014; 32:252–260.

62. Grove JE, Bruscia E, Krause DS. Plasticity of bone marrow-derived stem cells. Stem Cells. 2004; 22:487–500.

63. Petrof G, Abdul-Wahab A, McGrath JA. Cell therapy in dermatology. Cold Spring Harb Perspect Med. 2014; 4:a015156.

64. Körbling M, Katz RL, Khanna A, Ruifrok AC, Rondon G, Albitar M, et al. Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells. N Engl J Med. 2002; 346:738–746.

65. Chino T, Tamai K, Yamazaki T, Otsuru S, Kikuchi Y, Nimura K, et al. Bone marrow cell transfer into fetal circulation can ameliorate genetic skin diseases by providing fibroblasts to the skin and inducing immune tolerance. Am J Pathol. 2008; 173:803–814.

66. De Luca M, Pellegrini G, Mavilio F. Gene therapy of inherited skin adhesion disorders: a critical overview. Br J Dermatol. 2009; 161:19–24.

67. Fathke C, Wilson L, Hutter J, Kapoor V, Smith A, Hocking A, et al. Contribution of bone marrow-derived cells to skin: collagen deposition and wound repair. Stem Cells. 2004; 22:812–822.

68. Sasaki M, Abe R, Fujita Y, Ando S, Inokuma D, Shimizu H. Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J Immunol. 2008; 180:2581–2587.

69. Tamai K, Yamazaki T, Chino T, Ishii M, Otsuru S, Kikuchi Y, et al. PDGFRalpha-positive cells in bone marrow are mobilized by high mobility group box 1 (HMGB1) to regenerate injured epithelia. Proc Natl Acad Sci U S A. 2011; 108:6609–6614.

70. Hu X, Zhou Y, Dong K, Sun Z, Zhao D, Wang W, et al. Programming of the development of tumor-promoting neutrophils by mesenchymal stromal cells. Cell Physiol Biochem. 2014; 33:1802–1814.

71. Vangipuram M, Ting D, Kim S, Diaz R, Schüle B. Skin punch biopsy explant culture for derivation of primary human fibroblasts. J Vis Exp. 2013; (77):e3779.

72. Bilousova G, Chen J, Roop DR. Differentiation of mouse induced pluripotent stem cells into a multipotent keratinocyte lineage. J Invest Dermatol. 2011; 131:857–864.

73. Ohta S, Imaizumi Y, Okada Y, Akamatsu W, Kuwahara R, Ohyama M, et al. Generation of human melanocytes from induced pluripotent stem cells. PLoS One. 2011; 6:e16182.

74. Hewitt KJ, Shamis Y, Hayman RB, Margvelashvili M, Dong S, Carlson MW, et al. Epigenetic and phenotypic profile of fibroblasts derived from induced pluripotent stem cells. PLoS One. 2011; 6:e17128.

75. Hewitt KJ, Shamis Y, Knight E, Smith A, Maione A, Alt-Holland A, et al. PDGFRβ expression and function in fibroblasts derived from pluripotent cells is linked to DNA demethylation. J Cell Sci. 2012; 125:2276–2287.

76. Kim K, Doi A, Wen B, Ng K, Zhao R, Cahan P, et al. Epigenetic memory in induced pluripotent stem cells. Nature. 2010; 467:285–290.

77. Polo JM, Liu S, Figueroa ME, Kulalert W, Eminli S, Tan KY, et al. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nat Biotechnol. 2010; 28:848–855.

78. Nashun B, Hill PW, Hajkova P. Reprogramming of cell fate: epigenetic memory and the erasure of memories past. EMBO J. 2015; 34:1296–1308.

79. Muchkaeva IA, Dashinimaev EB, Terskikh VV, Sukhanov YV, Vasiliev AV. Molecular mechanisms of induced pluripotency. Acta Naturae. 2012; 4:12–22.

80. Miura K, Okada Y, Aoi T, Okada A, Takahashi K, Okita K, et al. Variation in the safety of induced pluripotent stem cell lines. Nat Biotechnol. 2009; 27:743–745.

81. Mayshar Y, Ben-David U, Lavon N, Biancotti JC, Yakir B, Clark AT, et al. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell. 2010; 7:521–531.

82. Gore A, Li Z, Fung HL, Young JE, Agarwal S, Antosiewicz-Bourget J, et al. Somatic coding mutations in human induced pluripotent stem cells. Nature. 2011; 471:63–67.

83. Lin YC, Murayama Y, Hashimoto K, Nakamura Y, Lin CS, Yokoyama KK, et al. Role of tumor suppressor genes in the cancer-associated reprogramming of human induced pluripotent stem cells. Stem Cell Res Ther. 2014; 5:58.

84. Cheng L, Hansen NF, Zhao L, Du Y, Zou C, Donovan FX, et al. Low incidence of DNA sequence variation in human induced pluripotent stem cells generated by nonintegrating plasmid expression. Cell Stem Cell. 2012; 10:337–344.

85. Szabo E, Rampalli S, Risueño RM, Schnerch A, Mitchell R, Fiebig-Comyn A, et al. Direct conversion of human fibroblasts to multilineage blood progenitors. Nature. 2010; 468:521–526.

86. Araki R, Uda M, Hoki Y, Sunayama M, Nakamura M, Ando S, et al. Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature. 2013; 494:100–104.

87. de Almeida PE, Ransohoff JD, Nahid A, Wu JC. Immunogenicity of pluripotent stem cells and their derivatives. Circ Res. 2013; 112:549–561.

88. Reinke JM, Sorg H. Wound repair and regeneration. Eur Surg Res. 2012; 49:35–43.

89. Yang RH, Qi SH, Shu B, Ruan SB, Lin ZP, Lin Y, et al. Epidermal stem cells (ESCs) accelerate diabetic wound healing via the Notch signalling pathway. Biosci Rep. 2016; 36:e00364.

90. Jiménez F, Garde C, Poblet E, Jimeno B, Ortiz J, Martínez ML, et al. A pilot clinical study of hair grafting in chronic leg ulcers. Wound Repair Regen. 2012; 20:806–814.

91. Jackson WM, Nesti LJ, Tuan RS. Concise review: clinical translation of wound healing therapies based on mesenchymal stem cells. Stem Cells Transl Med. 2012; 1:44–50.

92. Liu JQ, Zhao KB, Feng ZH, Qi FZ. Hair follicle units promote re-epithelialization in chronic cutaneous wounds: a clinical case series study. Exp Ther Med. 2015; 10:25–30.

93. Tartarini D, Mele E. Adult stem cell therapies for wound healing: biomaterials and computational models. Front Bioeng Biotechnol. 2016; 3:206.

94. Isakson M, de Blacam C, Whelan D, McArdle A, Clover AJ. Mesenchymal stem cells and cutaneous wound healing: current evidence and future potential. Stem Cells Int. 2015; 2015:831095.

95. Zahorec P, Koller J, Danisovic L, Bohac M. Mesenchymal stem cells for chronic wounds therapy. Cell Tissue Bank. 2015; 16:19–26.

96. Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells. 2007; 25:2648–2659.

97. Badiavas EV, Falanga V. Treatment of chronic wounds with bone marrow-derived cells. Arch Dermatol. 2003; 139:510–516.

98. Falanga V, Iwamoto S, Chartier M, Yufit T, Butmarc J, Kouttab N, et al. Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds. Tissue Eng. 2007; 13:1299–1312.

99. Dash NR, Dash SN, Routray P, Mohapatra S, Mohapatra PC. Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells. Rejuvenation Res. 2009; 12:359–366.

100. Hassan WU, Greiser U, Wang W. Role of adipose-derived stem cells in wound healing. Wound Repair Regen. 2014; 22:313–325.

101. Schmidt BA, Horsley V. Intradermal adipocytes mediate fibroblast recruitment during skin wound healing. Development. 2013; 140:1517–1527.

102. Kim EK, Li G, Lee TJ, Hong JP. The effect of human adipose-derived stem cells on healing of ischemic wounds in a diabetic nude mouse model. Plast Reconstr Surg. 2011; 128:387–394.

103. Schmidt B, Horsley V. Unravelling hair follicle-adipocyte communication. Exp Dermatol. 2012; 21:827–830.

104. Pang C, Ibrahim A, Bulstrode NW, Ferretti P. An overview of the therapeutic potential of regenerative medicine in cutaneous wound healing. Int Wound J. 2017; 14:450–459.

105. Pan JF, Liu NH, Sun H, Xu F. Preparation and characterization of electrospun PLCL/Poloxamer nanofibers and dextran/gelatin hydrogels for skin tissue engineering. PLoS One. 2014; 9:e112885.

106. Rodrigues C, de Assis AM, Moura DJ, Halmenschlager G, Saffi J, Xavier LL, et al. New therapy of skin repair combining adipose-derived mesenchymal stem cells with sodium carboxymethylcellulose scaffold in a pre-clinical rat model. PLoS One. 2014; 9:e96241.

107. Yoshikawa T, Mitsuno H, Nonaka I, Sen Y, Kawanishi K, Inada Y, et al. Wound therapy by marrow mesenchymal cell transplantation. Plast Reconstr Surg. 2008; 121:860–877.

108. Ravari H, Hamidi-Almadari D, Salimifar M, Bonakdaran S, Parizadeh MR, Koliakos G. Treatment of non-healing wounds with autologous bone marrow cells, platelets, fibrin glue and collagen matrix. Cytotherapy. 2011; 13:705–711.

109. Ma K, Liao S, He L, Lu J, Ramakrishna S, Chan CK. Effects of nanofiber/stem cell composite on wound healing in acute full-thickness skin wounds. Tissue Eng Part A. 2011; 17:1413–1424.

110. Naseri N, Mathew AP, Girandon L, Frohlich M, Oksman K. Porous electrospun nanocomposite mats based on chitosan-cellulose nanocrystals for wound dressing: effect of surface characteristics of nanocrystals. Cellulose. 2015; 22:521–534.

111. Yañez R, Lamana ML, García-Castro J, Colmenero I, Ramírez M, Bueren JA. Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells. 2006; 24:2582–2591.

112. Sun L, Akiyama K, Zhang H, Yamaza T, Hou Y, Zhao S, et al. Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans. Stem Cells. 2009; 27:1421–1432.

113. Kim HS, Yun JW, Shin TH, Lee SH, Lee BC, Yu KR, et al. Human umbilical cord blood mesenchymal stem cell-derived PGE2 and TGF-β1 alleviate atopic dermatitis by reducing mast cell degranulation. Stem Cells. 2015; 33:1254–1266.

114. Ringdén O, Erkers T, Nava S, Uzunel M, Iwarsson E, Conrad R, et al. Fetal membrane cells for treatment of steroid-refractory acute graft-versus-host disease. Stem Cells. 2013; 31:592–601.

115. Sah SK, Park KH, Yun CO, Kang KS, Kim TY. Effects of human mesenchymal stem cells transduced with superoxide dismutase on imiquimod-induced psoriasis-like skin inflammation in mice. Antioxid Redox Signal. 2016; 24:233–248.

116. Kim HS, Lee JH, Roh KH, Jun HJ, Kang KS, Kim TY. Clinical trial of human umbilical cord blood-derived stem cells for the treatment of moderate-to-severe atopic dermatitis: phase I/IIa studies. Stem Cells. 2017; 35:248–255.

117. Chen H, Niu JW, Ning HM, Pan X, Li XB, Li Y, et al. Treatment of psoriasis with mesenchymal stem cells. Am J Med. 2016; 129:e13–e14.

118. De Jesus MM, Santiago JS, Trinidad CV, See ME, Semon KR, Fernandez MO Jr, et al. Autologous adipose-derived mesenchymal stromal cells for the treatment of psoriasis vulgaris and psoriatic arthritis: a case report. Cell Transplant. 2016; 25:2063–2069.

119. Wang D, Zhang H, Liang J, Li X, Feng X, Wang H, et al. Allogeneic mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus: 4 years of experience. Cell Transplant. 2013; 22:2267–2277.

120. Ogliari KS, Marinowic D, Brum DE, Loth F. Stem cells in dermatology. An Bras Dermatol. 2014; 89:286–291.

121. Cras A, Farge D, Carmoi T, Lataillade JJ, Wang DD, Sun L. Update on mesenchymal stem cell-based therapy in lupus and scleroderma. Arthritis Res Ther. 2015; 17:301.

122. Burt RK, Shah SJ, Dill K, Grant T, Gheorghiade M, Schroeder J, et al. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet. 2011; 378:498–506.

123. Kühl T, Mezger M, Hausser I, Handgretinger R, Bruckner-Tuderman L, Nyström A. High local concentrations of intradermal MSCs restore skin integrity and facilitate wound healing in dystrophic epidermolysis bullosa. Mol Ther. 2015; 23:1368–1379.

124. Fritsch A, Loeckermann S, Kern JS, Braun A, Bösl MR, Bley TA, et al. A hypomorphic mouse model of dystrophic epidermolysis bullosa reveals mechanisms of disease and response to fibroblast therapy. J Clin Invest. 2008; 118:1669–1679.

125. Kern JS, Loeckermann S, Fritsch A, Hausser I, Roth W, Magin TM, et al. Mechanisms of fibroblast cell therapy for dystrophic epidermolysis bullosa: high stability of collagen VII favors long-term skin integrity. Mol Ther. 2009; 17:1605–1615.

126. Conget P, Rodriguez F, Kramer S, Allers C, Simon V, Palisson F, et al. Replenishment of type VII collagen and re-epithelialization of chronically ulcerated skin after intradermal administration of allogeneic mesenchymal stromal cells in two patients with recessive dystrophic epidermolysis bullosa. Cytotherapy. 2010; 12:429–431.

127. Petrof G, Martinez-Queipo M, Mellerio JE, Kemp P, McGrath JA. Fibroblast cell therapy enhances initial healing in recessive dystrophic epidermolysis bullosa wounds: results of a randomized, vehicle-controlled trial. Br J Dermatol. 2013; 169:1025–1033.

128. Venugopal SS, Yan W, Frew JW, Cohn HI, Rhodes LM, Tran K, et al. A phase II randomized vehicle-controlled trial of intradermal allogeneic fibroblasts for recessive dystrophic epidermolysis bullosa. J Am Acad Dermatol. 2013; 69:898–908.e7.

129. Schwieger-Briel A, Weibel L, Chmel N, Leppert J, Kernland-Lang K, Grüninger G, et al. A COL7A1 variant leading to in-frame skipping of exon 15 attenuates disease severity in recessive dystrophic epidermolysis bullosa. Br J Dermatol. 2015; 173:1308–1311.

130. Peking P, Koller U, Hainzl S, Kitzmueller S, Kocher T, Mayr E, et al. A gene gun-mediated nonviral RNA trans-splicing strategy for Col7a1 repair. Mol Ther Nucleic Acids. 2016; 5:e287.

131. Petrof G, Lwin SM, Martinez-Queipo M, Abdul-Wahab A, Tso S, Mellerio JE, et al. Potential of systemic allogeneic mesenchymal stromal cell therapy for children with recessive dystrophic epidermolysis bullosa. J Invest Dermatol. 2015; 135:2319–2321.

132. El-Darouti M, Fawzy M, Amin I, Abdel Hay R, Hegazy R, Gabr H, et al. Treatment of dystrophic epidermolysis bullosa with bone marrow non-hematopoeitic stem cells: a randomized controlled trial. Dermatol Ther. 2016; 29:96–100.

133. Wagner JE, Ishida-Yamamoto A, McGrath JA, Hordinsky M, Keene DR, Woodley DT, et al. Bone marrow transplantation for recessive dystrophic epidermolysis bullosa. N Engl J Med. 2010; 363:629–639.

134. Iinuma S, Aikawa E, Tamai K, Fujita R, Kikuchi Y, Chino T, et al. Transplanted bone marrow-derived circulating PDGFR α+ cells restore type VII collagen in recessive dystrophic epidermolysis bullosa mouse skin graft. J Immunol. 2015; 194:1996–2003.

135. Tolar J, McGrath JA, Keene DR, Hook K, Osborn MJ, Riddle MJ, et al. Hematopoietic and mesenchymal cell transplantation after myeloablative and non-myeloablative conditioning for recessive dystrophic and junctional epidermolysis bullosa (RDEB, JEB). Society of Investigative Dermatology, Venice, Italy. J Invest Dermatol. 2012; 132:A534.

136. Fujita Y, Abe R, Inokuma D, Sasaki M, Hoshina D, Natsuga K, et al. Bone marrow transplantation restores epidermal basement membrane protein expression and rescues epidermolysis bullosa model mice. Proc Natl Acad Sci U S A. 2010; 107:14345–14350.

137. Gussoni E, Soneoka Y, Strickland CD, Buzney EA, Khan MK, Flint AF, et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature. 1999; 401:390–394.

138. Gussoni E, Bennett RR, Muskiewicz KR, Meyerrose T, Nolta JA, Gilgoff I, et al. Long-term persistence of donor nuclei in a Duchenne muscular dystrophy patient receiving bone marrow transplantation. J Clin Invest. 2002; 110:807–814.

139. Ferrari G, Stornaiuolo A, Mavilio F. Failure to correct murine muscular dystrophy. Nature. 2001; 411:1014–1015.

140. De Rosa L, Carulli S, Cocchiarella F, Quaglino D, Enzo E, Franchini E, et al. Long-term stability and safety of transgenic cultured epidermal stem cells in gene therapy of junctional epidermolysis bullosa. Stem Cell Reports. 2013; 2:1–8.

141. Siprashvili Z, Nguyen NT, Gorell ES, Loutit K, Khuu P, Furukawa LK, et al. Safety and wound outcomes following genetically corrected autologous epidermal grafts in patients with recessive dystrophic epidermolysis bullosa. JAMA. 2016; 316:1808–1817.

142. Aasen T, Raya A, Barrero MJ, Garreta E, Consiglio A, Gonzalez F, et al. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol. 2008; 26:1276–1284.

143. Itoh M, Kiuru M, Cairo MS, Christiano AM. Generation of keratinocytes from normal and recessive dystrophic epidermolysis bullosa-induced pluripotent stem cells. Proc Natl Acad Sci U S A. 2011; 108:8797–8802.

144. Tolar J, Xia L, Riddle MJ, Lees CJ, Eide CR, McElmurry RT, et al. Induced pluripotent stem cells from individuals with recessive dystrophic epidermolysis bullosa. J Invest Dermatol. 2011; 131:848–856.

145. Tolar J, Xia L, Lees CJ, Riddle M, McElroy A, Keene DR, et al. Keratinocytes from induced pluripotent stem cells in junctional epidermolysis bullosa. J Invest Dermatol. 2013; 133:562–565.

146. Agarwal S, Loh YH, McLoughlin EM, Huang J, Park IH, Miller JD, et al. Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients. Nature. 2010; 464:292–296.

147. Bilousova G, Chen J, Roop DR. Exploring the therapeutic potential of induced pluripotent stem cells for the treatment of epidermolytic hyperkeratosis and epidermolysis bullosa simplex. J Invest Dermatol. 2011b; 131:S70.

148. Sebastiano V, Zhen HH, Haddad B, Bashkirova E, Melo SP, Wang P, et al. Human COL7A1-corrected induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa. Sci Transl Med. 2014; 6:264ra163.

149. Itoh M, Umegaki-Arao N, Guo Z, Liu L, Higgins CA, Christiano AM. Generation of 3D skin equivalents fully reconstituted from human induced pluripotent stem cells (iPSCs). PLoS One. 2013; 8:e77673.

150. Spiliopoulos S, Davanos N. Induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa. Ann Transl Med. 2015; 3:349.

151. Lai-Cheong JE, McGrath JA, Uitto J. Revertant mosaicism in skin: natural gene therapy. Trends Mol Med. 2011; 17:140–148.

152. Pasmooij AM, Jonkman MF, Uitto J. Revertant mosaicism in heritable skin diseases: mechanisms of natural gene therapy. Discov Med. 2012; 14:167–179.

153. Gostynski A, Deviaene FC, Pasmooij AM, Pas HH, Jonkman MF. Adhesive stripping to remove epidermis in junctional epidermolysis bullosa for revertant cell therapy. Br J Dermatol. 2009; 161:444–447.

154. Gostyński A, Pasmooij AM, Jonkman MF. Successful therapeutic transplantation of revertant skin in epidermolysis bullosa. J Am Acad Dermatol. 2014; 70:98–101.

155. Hoerter JD, Bradley P, Casillas A, Chambers D, Denholm C, Johnson K, et al. Extrafollicular dermal melanocyte stem cells and melanoma. Stem Cells Int. 2012; 2012:407079.

156. Mull AN, Zolekar A, Wang YC. Understanding melanocyte stem cells for disease modeling and regenerative medicine applications. Int J Mol Sci. 2015; 16:30458–30469.

157. Tsuchiyama K, Wakao S, Kuroda Y, Ogura F, Nojima M, Sawaya N, et al. Functional melanocytes are readily reprogrammable from multilineage-differentiating stress-enduring (muse) cells, distinct stem cells in human fibroblasts. J Invest Dermatol. 2013; 133:2425–2435.

158. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994; 367:645–648.

159. Yumoto K, Eber MR, Berry JE, Taichman RS, Shiozawa Y. Molecular pathways: niches in metastatic dormancy. Clin Cancer Res. 2014; 20:3384–3389.

160. Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med. 2011; 17:313–319.

161. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005; 5:275–284.

162. Singh A, Park H, Kangsamaksin T, Singh A, Readio N, Morris RJ. Keratinocyte stem cells and the targets for non-melanoma skin cancer. Photochem Photobiol. 2012; 88:1099–1110.

163. Jian Z, Strait A, Jimeno A, Wang XJ. Cancer stem cells in squamous cell carcinoma. J Invest Dermatol. 2017; 137:31–37.

164. Lenz HJ, Kahn M. Safely targeting cancer stem cells via selective catenin coactivator antagonism. Cancer Sci. 2014; 105:1087–1092.

165. Krishnamurthy J, Sharpless NE. Stem cells and the rate of living. Cell Stem Cell. 2007; 1:9–11.

166. Jung Y, Brack AS. Cellular mechanisms of somatic stem cell aging. Curr Top Dev Biol. 2014; 107:405–438.

167. Dahl MV. Stem cells and the skin. J Cosmet Dermatol. 2012; 11:297–306.

168. Shuai Y, Liao L, Su X, Yu Y, Shao B, Jing H, et al. Melatonin treatment improves mesenchymal stem cells therapy by preserving stemness during long-term in vitro expansion. Theranostics. 2016; 6:1899–1917.

169. Drela K, Sarnowska A, Siedlecka P, Szablowska-Gadomska I, Wielgos M, Jurga M, et al. Low oxygen atmosphere facilitates proliferation and maintains undifferentiated state of umbilical cord mesenchymal stem cells in an hypoxia inducible factor-dependent manner. Cytotherapy. 2014; 16:881–892.

170. D'Ippolito G, Diabira S, Howard GA, Roos BA, Schiller PC. Low oxygen tension inhibits osteogenic differentiation and enhances stemness of human MIAMI cells. Bone. 2006; 39:513–522.

171. Wong TY, Solis MA, Chen YH, Huang LL. Molecular mechanism of extrinsic factors affecting anti-aging of stem cells. World J Stem Cells. 2015; 7:512–520.

172. Kurtz A, Oh SJ. Age related changes of the extracellular matrix and stem cell maintenance. Prev Med. 2012; 54:Suppl. S50–S56.

173. Ju Z, Jiang H, Jaworski M, Rathinam C, Gompf A, Klein C, et al. Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat Med. 2007; 13:742–747.