Current Dermatology Reports

, Volume 7, Issue 4, pp 278–286 | Cite as

Use of Stem Cells in Wound Healing

  • Adam Aronson
  • Leah Laageide
  • Jennifer PowersEmail author
Wound Care and Healing (H Lev-Tov, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Wound Care and Healing


Purpose of Review

This review provides an overview of the principal stages of wound healing, the populations of endogenous and therapeutic stem cells, applications of stem cells in specific types of wounds, and current approaches of stem cell delivery for tissue regeneration.

Recent Findings

New uses of progenitor stem cells have been developed for the treatment of wounds. Stem cells improve wound healing through both local and paracrine effects. Stem cell populations of therapeutic utility include embryonic stem cells, induced pluripotent stem cells, adult bone marrow and adipose-derived mesenchymal stem cells, as well as stem cells from skin, cord blood, and extra fetal tissue. Induced pluripotent stem cells mitigate many of the ethical and immunogenic concerns related to use of embryonically derived stem cells.


Skin, the largest organ in the human body, serves as a protective barrier for mammals. Both aging and disease contribute to loss of skin barrier function, which can result in consequences such as chronic wounds. Recent advances in many types of stem cell therapy may revolutionize treatment of difficult wounds. Optimal techniques for obtaining and delivering stem cells are still being refined.


Stem cells Wound healing Chronic wounds Biologic therapies 


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Li Y, Zhang J, Yue J, Gou X, Wu X. Epidermal stem cells in skin wound healing. Adv Wound Care. 2017;6(9):297–307. Scholar
  2. 2.
    Lee DE, Ayoub N, Agrawal DK. Mesenchymal stem cells and cutaneous wound healing: novel methods to increase cell delivery and therapeutic efficacy. Stem Cell Res Ther. 2016;7(1):37. Scholar
  3. 3.
    Eming SA, Martin P, Tomic-Canic M. Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med. 2014;6:265. Scholar
  4. 4.
    Chen M, Przyborowski M, Berthiaume F. Stem cells for skin tissue engineering and wound healing. Crit Rev Biomed Eng. 2009;37(4–5):399–421. Scholar
  5. 5.
    McGrath JA, Eady RAJ, Pope FM. Anatomy and organization of human skin. In: Burns T, Breathnach S, Cox N, Griffiths C, editors. Rook’s textbook of dermatology. 7th ed. Hoboken: Blackwell Publishing; 2004. p. 4190. ISBN 978-0-632-06429-8. Retrieved 2010-06-01.CrossRefGoogle Scholar
  6. 6.
    Bouwstra JA, Ponec M. The skin barrier in healthy and diseased state. Biochim Biophys Acta Biomembr. 2006;1758(12):2080–95. Scholar
  7. 7.
    Harvey C. Wound healing. Orthop Nurs. 2005;24(2):143–57.CrossRefGoogle Scholar
  8. 8.
    Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453(7193):314–21.CrossRefGoogle Scholar
  9. 9.
    Gonzalez ACDO, Costa TF, Andrade ZDA, Medrado ARAP. Wound healing—a literature review. An Bras Dermatol. 2016;91(5):614–20. Scholar
  10. 10.
    Han G, Ceilley R. Chronic wound healing: a review of current management and treatments. Adv Ther. 2017;34(3):599–610. Scholar
  11. 11.
    Kanji S, Das H. Advances of stem cell therapeutics in cutaneous wound healing and regeneration. Mediat Inflamm. 2017;2017:1–14. Scholar
  12. 12.
    Jaks V, Barker N, Kasper M, van Es JH, Snippert HJ, Clevers H, et al. Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nat Genet. 2008;40(11):1291–9. Scholar
  13. 13.
    Cerqueira MT, Pirraco RP, Marques AP. Stem cells in skin wound healing: are we there yet? Adv Wound Care. 2016;5(4):164–75. Scholar
  14. 14.
    Bergen TV, Velde SVD, Vandewalle E, Moons L, Stalmans I. Improving patient outcomes following glaucoma surgery: state of the art and future perspectives. Clin Ophthalmol. 2014:857.
  15. 15.
    Beitz JM. Pharmacologic impact (aka “breaking bad”) of medications on wound healing and wound development: a literature-based overview. Advances in pediatrics. Published March 2017. Accessed 6 June 2018.
  16. 16.
    Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M. Perspective article: growth factors and cytokines in wound healing. Wound Repair Regen. 2008;16(5):585–601. Scholar
  17. 17.
    Guo S, Dipietro L. Factors affecting wound healing. J Dent Res. 2010;89(3):219–29. Scholar
  18. 18.
    Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev. 2003;83(3):835–70.CrossRefGoogle Scholar
  19. 19.
    Smola H, Thiekotter G, Fusenig NE. Mutual induction of growth factor gene expression by epidermal-dermal cell interaction. J Cell Biol. 1993;122(2):417–29.CrossRefGoogle Scholar
  20. 20.
    Kumar A, Mohanty S, Gupta S, Paulkhurana SM. Stem cells of the hair follicular tissue: application in cell based therapy for vitiligo. Hair Ther Transplant. 2015;05(01).
  21. 21.
    Snippert HJ, Haegebarth A, Kasper M, Jaks V, van Es JH, Barker N, et al. Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin. Science. 2010;327(5971):1385–9. Scholar
  22. 22.
    Woo W-M, Oro AE. SnapShot: hair follicle stem cells. Cell. 2011;146(2):334–334.e2. Scholar
  23. 23.
    Chu G-Y, Chen Y-F, Chen H-Y, Chan M-H, Gau C-S, Weng S-M. Stem cell therapy on skin: mechanisms, recent advances and drug reviewing issues. J Food Drug Anal. 2018;26(1):14–20. Scholar
  24. 24.
    Opalenik SR, Davidson JM. Fibroblast differentiation of bone marrow-derived cells during wound repair. FASEB J. 2005;19(11):1561–3. Scholar
  25. 25.
    Fathke C. Contribution of bone marrow-derived cells to skin: collagen deposition and wound repair. Stem Cells. 2004;22(5):812–22. Scholar
  26. 26.
    Ito M, Yang Z, Andl T, Cui C, Kim N, Millar SE, et al. Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature. 2007;447(7142):316–20. Scholar
  27. 27.
    Shi Y, Shu B, Yang R, et al. Wnt and Notch signaling pathway involved in wound healing by targeting c-Myc and Hes1 separately. Stem Cell Res Ther. 2015;6(1):120. Scholar
  28. 28.
    Whyte JL, Smith AA, Liu B, Manzano WR, Evans ND, Dhamdhere GR, et al. Augmenting endogenous Wnt signaling improves skin wound healing. PLoS One. 2013;8(10):e76883. Scholar
  29. 29.
    Wong VW, Levi B, Rajadas J, Longaker MT, Gurtner GC. Stem cell niches for skin regeneration. Int J Biomater. 2012;2012:1–8. Scholar
  30. 30.
    Agrawal GK, Jwa N-S, Lebrun M-H, Job D, Rakwal R. Plant secretome: unlocking secrets of the secreted proteins. Proteomics. 2010;10(4):799–827. Scholar
  31. 31.
    Baraniak PR, Mcdevitt TC. Stem cell paracrine actions and tissue regeneration. Regen Med. 2010;5(1):121–43. Scholar
  32. 32.
    • Denu RA, Nemcek S, Bloom DD, et al. Fibroblasts and mesenchymal stromal/stem cells are phenotypically indistinguishable. Acta Haematol. 2016;136(2):85–97. This study demonstrates indistinguishable cell surface makers and morphology between fibroblasts and mesenchymal stem cells. This supports our understanding that MSCs parallel fibroblasts in their wound healing capacity: both cell types secrete extracellular matrix and suppress the inflammatory cascade. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Duscher D, Barrera J, Wong VW, Maan ZN, Whittam AJ, Januszyk M, et al. Stem cells in wound healing: the future of regenerative medicine? A mini-review. Gerontology. 2015;62(2):216–25. Scholar
  34. 34.
    Dominici M, Blanc KL, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7. Scholar
  35. 35.
    Gorskaya YF, Fridenshtein AY, Kulagina NN. Precursor cells of fibroblasts detected by in vitro cloning of cells from hematopoietic organs of normal and irradiated mice. Bull Exp Biol Med. 1976;81(5):765–8. Scholar
  36. 36.
    Gimble J, Guilak F. Adipose-derived adult stem cells: isolation, characterization, and differentiation potential. Cytotherapy. 2003;5(5):362–9. Scholar
  37. 37.
    Meliga E, Strem BM, Duckers HJ, Serruys PW. Adipose-derived cells. Cell Transplant. 2007;16(9):963–70. Scholar
  38. 38.
    Jones EA, English A, Henshaw K, Kinsey SE, Markham AF, Emery P, et al. Enumeration and phenotypic characterization of synovial fluid multipotential mesenchymal progenitor cells in inflammatory and degenerative arthritis. Arthritis Rheum. 2004;50(3):817–27. Scholar
  39. 39.
    Rezvani HR, Ali N, Nissen LJ, Harfouche G, de Verneuil H, Taïeb A, et al. HIF-1a in epidermis: oxygen sensing, cutaneous angiogenesis, cancer, and non-cancer disorders. J Investig Dermatol. 2011;131:1793–805.CrossRefGoogle Scholar
  40. 40.
    Frenette PS, Pinho S, Lucas D, Scheiermann C. Mesenchymal stem cell: keystone of the hematopoietic stem cell niche and a stepping-stone for regenerative medicine. Annu Rev Immunol. 2013;31(1):285–316. Scholar
  41. 41.
    Chen L, Tredget EE, Wu PYG, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One. 2008;3(4):e1886. Scholar
  42. 42.
    Wu Y, Zhao RC, Tredget EE. Concise review: bone marrow-derived stem/progenitor cells in cutaneous repair and regeneration. Stem Cells. 2010;28:905–15.PubMedPubMedCentralGoogle Scholar
  43. 43.
    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;13:1299–312.CrossRefGoogle Scholar
  44. 44.
    • Summa PGD, Schiraldi L, Cherubino M, et al. Adipose derived stem cells reduce fibrosis and promote nerve regeneration in rats. The Anatomical Record. 2018. This study illustrates the therapeutic potential of adipose derived stem cells by demonstrating reduced scar formation and increased nerve regeneration. CrossRefGoogle Scholar
  45. 45.
    Altman AM, Matthias N, Yan Y, et al. Dermal matrix as a carrier for in vivo delivery of human adipose-derived stem cells. Biomaterials. 2008;29(10):1431–42.CrossRefGoogle Scholar
  46. 46.
    Riccobono D, Agay D, Scherthan H, Forcheron F, Vivier M, Ballester B, et al. Application of adipocyte-derived stem cells in treatment of cutaneous radiation syndrome. Health Phys. 2012;103(2):120–6.CrossRefGoogle Scholar
  47. 47.
    Alexaki V-I, Simantiraki D, Panayiotopoulou M, Rasouli O, Venihaki M, Castana O, et al. Adipose tissue-derived mesenchymal cells support skin reepithelialization through secretion of KGF-1 and PDGF-BB: comparison with dermal fibroblasts. Cell Transplant. 2012;21(11):2441–54. Scholar
  48. 48.
    Anker PSI’t. Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation. Blood. 2003;102(4):1548–9. Scholar
  49. 49.
    Alviano F, Fossati V, Marchionni C, Arpinati M, Bonsi L, Franchina M, et al. Term amniotic membrane is a high throughput source for multipotent mesenchymal stem cells with the ability to differentiate into endothelial cells in vitro. BMC Dev Biol. 2007;7:11.CrossRefGoogle Scholar
  50. 50.
    Kim W-S, Park B-S, Sung J-H, Yang JM, Park SB, Kwak SJ, et al. Wound healing effect of adipose-derived stem cells: a critical role of secretory factors on human dermal fibroblasts. J Dermatol Sci. 2007;48(1):15–24. Scholar
  51. 51.
    Guenou H, Nissan X, Larcher F, Feteira J, Lemaitre G, Saidani M, et al. Human embryonic stem-cell derivatives for full reconstruction of the pluristratified epidermis: a preclinical study. Lancet. 2009;374(9703):1745–53. Scholar
  52. 52.
    Douglas CW. Embryonic stem cell transplantation: potential applicability in cell replacement therapy and regenerative medicine. Front Biosci. 2007;12(8–12):4525. Scholar
  53. 53.
    Lo B, Parham L. Ethical issues in stem cell research. Endocr Rev. 2009;30(3):204–13. Scholar
  54. 54.
    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.CrossRefGoogle Scholar
  55. 55.
    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;26:1276–84.CrossRefGoogle Scholar
  56. 56.
    Tsai S-Y, Clavel C, Kim S, Ang YS, Grisanti L, Lee DF, et al. Oct4 and Klf4 reprogram dermal papilla cells into induced pluripotent stem cells. In: Stem Cells; 2009. Scholar
  57. 57.
    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(264):264ra163. Scholar
  58. 58.
    Umegaki-Arao N, Pasmooij AMG, Itoh M, Cerise JE, Guo Z, Levy B, et al. Induced pluripotent stem cells from human revertant keratinocytes for the treatment of epidermolysis bullosa. Sci Transl Med. 2014;6(264):264ra164. Scholar
  59. 59.
    Macneil S. Progress and opportunities for tissue-engineered skin. Nature. 2007;445(7130):874–80. Scholar
  60. 60.
    Werdin F, Tenenhaus M, Rennekampff H-O. Chronic wound care. Lancet. 2008;372(9653):1860–2. Scholar
  61. 61.
    Steed DL, Attinger C, Colaizzi T, Crossland M, Franz M, Harkless L, et al. Guidelines for the treatment of diabetic ulcers. Wound Repair Regen. 2006;14(6):680–92.CrossRefGoogle Scholar
  62. 62.
    Robson MC, Barbul A. Guidelines for the best care of chronic wounds. Wound Repair Regen. 2006;14(6):647–8.CrossRefGoogle Scholar
  63. 63.
    Krasnodembskaya A, Song Y, Fang X, et al. Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells. 2010;28(12):2229–38.CrossRefGoogle Scholar
  64. 64.
    Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell. 2008;2(2):141–50. Scholar
  65. 65.
    Liu L, Yu Y, Hou Y, et al. Human umbilical cord mesenchymal stem cells transplantation promotes cutaneous wound healing of severe burned rats. PLoS One. 9(2):e88348, 2014.CrossRefGoogle Scholar
  66. 66.
    Németh K, Leelahavanichkul A, Yuen PST, Mayer B, Parmelee A, Doi K, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E2-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med. 2008;15(1):42–9. Scholar
  67. 67.
    Benbernou N, Esnault S, Shin HCK, Fekkar H, Guenounou M. Differential regulation of IFN-gamma, IL-10 and inducible nitric oxide synthase in human T cells by cyclic AMP-dependent signal transduction pathway. Immunology. 1997;91(3):361–8. Scholar
  68. 68.
    Natesan S, Zamora DO, Wrice NL, Baer DG, Christy RJ. Bilayer hydrogel with autologous stem cells derived from debrided human burn skin for improved skin regeneration. J Burn Care Res. 2013;34(1):18–30.CrossRefGoogle Scholar
  69. 69.
    Watt FM, Lo Celso C, Silva-Vargas V. Epidermal stem cells: an update. Curr Opin Genet Dev. 2006;16:518–24.CrossRefGoogle Scholar
  70. 70.
    Yang Y, Zhang W, Li Y, Fang G, Zhang K. Scalded skin of rat treated by using fibrin glue combined with allogeneic bone marrow mesenchymal.Google Scholar
  71. 71.
    Hu C, Yong X, Li C, Lü M, Liu D, Chen L, et al. CXCL12/CXCR4 axis promotes mesenchymal stem cell mobilization to burn wounds and contributes to wound repair. J Surg Res. 2013;183(1):427–34. Scholar
  72. 72.
    Basu S, Ali H, Sangwan VS. Clinical outcomes of repeat autologous cultivated limbal epithelial transplantation for ocular surface burns. Am J Ophthalmol. 2012;153(4).
  73. 73.
    Rasulov MF, Vasilenko VT, Zaidenov VA, Onishchenko NA. Cell transplantation inhibits inflammatory reaction and stimulates repair processes in burn wound. Bull Exp Biol Med. 2006;142(1):112–5. Scholar
  74. 74.
    Collawn SS, Banerjee NS, de la Torre J, Vasconez L, Chow LT. Adipose-derived stromal cells accelerate wound healing in an organotypic raft culture model. Ann Plast Surg. 2012;68(5):501–4. Scholar
  75. 75.
    Shortt AJ, Secker GA, Notara MD, Limb GA, Khaw PT, Tuft SJ, et al. Transplantation of ex vivo cultured limbal epithelial stem cells: a review of techniques and clinical results. Surv Ophthalmol. 2007;52(5):483–502. Scholar
  76. 76.
    Dua HS, Azuara-Blanco A. Limbal stem cells of the corneal epithelium. Surv Ophthalmol. 2000;44(5):415–25.CrossRefGoogle Scholar
  77. 77.
    Cohn Yakubovich D, Sheyn D, Bez M, Schary Y, Yalon E, Sirhan A, et al. Systemic administration of mesenchymal stem cells combined with parathyroid hormone therapy synergistically regenerates multiple rib fractures. Stem Cell Res Ther. 2017;8:51. Scholar
  78. 78.
    Garg RK, Rennert RC, Duscher D, Sorkin M, Kosaraju R, Auerbach LJ, et al. Capillary force seeding of hydrogels for adipose-derived stem cell delivery in wounds. Stem Cells Transl Med. 2014;3(9):1079–89. Scholar
  79. 79.
    Rustad KC, Wong VW, Sorkin M, Glotzbach JP, Major MR, Rajadas J, et al. Enhancement of mesenchymal stem cell angiogenic capacity and stemness by a biomimetic hydrogel scaffold. Biomaterials. 2012;33(1):80–90. Scholar
  80. 80.
  81. 81.
    Little M-T, Storb R. History of haematopoietic stem-cell transplantation. Nature News. Published March 1, 2002. Accessed 5 June 2018.
  82. 82.
    Markers & methods to verify mesenchymal stem cell identity, potency, & quality. R&D Systems. Accessed 5 June 2018.
  83. 83.
    Boston Children's Hospital. Boston Children’s Hospital. Accessed 5 June 2018.
  84. 84.
    Bello YM, Falabella AF, Eaglstein WH. Tissue-engineered skin. Am J Clin Dermatol. 2001;2(5):305–13. Scholar
  85. 85.
    Marston WA, Hanft J, Norwood P, Pollak R. The efficacy and safety of dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care. 2003;26(6):1701–5. Scholar
  86. 86.
    Wheeland RG. The technique and current status of pinch grafting. J Dermatol Surg Oncol. 1987;13(8):873–81. Scholar
  87. 87.
    • Osborne SN, Schmidt MA, Harper JR. An automated and minimally invasive tool for generating autologous viable epidermal micrografts. Adv Skin Wound Care. 2016;29(2):57–64. This study outlines a novel, minimally invasive epidermal harvesting tool that aids in rapid wound healing and reduced scarring at both donor and recipient graft sites. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of DermatologyUniversity of Iowa Hospitals and ClinicsIowa CityUSA
  2. 2.Carver College of MedicineUniversity of Iowa Hospitals and ClinicsIowa CityUSA
  3. 3.Department of DermatologyUniversity of Iowa Hospitals and Clinics and VA Medical CenterIowa CityUSA

Personalised recommendations