Wound Treatment by Stem Cells

  • Leyla Türker Şener
  • Hakan Darici
  • Işil Albeniz
  • Erdal Karaöz
Chapter
Part of the Stem Cells in Clinical Applications book series (SCCA)

Abstract

Various experimental or clinical studies in the literature have demonstrated the benefits of stem cells, especially mesenchymal stem cells. This chapter will focus on existing stem cell technologies and their applications in the treatment of wound healing. To understand mechanisms of stem cells in wound healing, we will go over the structure of most commonly wounded tissues, namely, skin, which consist of epithelia and connective tissue. Then we will explain wound healing process with three stages as inflammation, proliferation, and remodeling and the roles of tissue components during wound healing. Treatment of wounds is directly related with the cause, location, and degree of the wound. Therefore, we will describe common wound types with causes under two categories as acute and chronic. We will explain stem cell types which play an important role in tissue regeneration and wound healing in adult life owing to their high competency and self-renewal features. Here, we will give examples of various studies on various wound types with or without underlying diseases. Finally, we will describe recently developed methods such as the use of cells' own products, exosomes, and demonstrate the results of exosome therapies on chronic wounds with most recent examples on human trials.

Keywords

Wound healing Cellular therapy Acellular therapy Mesenchymal stem cell Exosome 

References

  1. Akash MS, Rehman K, Chen S (2013) Role of inflammatory mechanisms in pathogenesis of type 2 diabetes mellitus. J Cell Biochem 114(3):525–531CrossRefPubMedGoogle Scholar
  2. Arya AK, Tripathi R, Kumar S, Tripathi K (2014) Recent advances on the association of apoptosis in chronic non healing diabetic wound. World J Diabetes 5(6):756–762CrossRefPubMedPubMedCentralGoogle Scholar
  3. Balbach ST, Cavaleri FM, Gentile L, Araúzo-Bravo MJ, Schöler HR, Crosetto N, Boiani M (2009) Observing and manipulating pluripotency in normal and cloned mouse embryos. In: Baharvand H (ed) Trends in stem cell biology and technology. Humana Press, New York, p 101CrossRefGoogle Scholar
  4. Barbul A, Breslin JR, Woodyard JP, Wasserkrug HL, Efron G (1989) The effect of in vivo T helper and T suppressor lymphocyte depletion on wound healing. Ann Surg 209:479–483CrossRefPubMedPubMedCentralGoogle Scholar
  5. Berman DM, Willman MA, Han D et al (2010) Mesenchymal stem cells enhance allogeneic islet engraftment in nonhuman primates. Diabetes 59:2558–2568CrossRefPubMedPubMedCentralGoogle Scholar
  6. Besse JL, Leemrijse T, Deleu PA (2011) Diabetic foot: the orthopedic surgery angle. Orthop Traumatol Surg Res 97:314–329CrossRefPubMedGoogle Scholar
  7. Black IB, Woodbury D (2001) Adult rat and human bone marrow stromal stem cells differentiate into neurons. Blood Cells Mol Dis 27:632–636CrossRefPubMedGoogle Scholar
  8. Blumberg SN, Berger A, Hwang L, Pastar I, Warren SM, Chen W (2012) The role of stem cells in the treatment of diabetic foot ulcers. Diabetes Res Clin Pract 96(1):1–9CrossRefPubMedGoogle Scholar
  9. Bura A, Planat-Benard V, Bourin P, Silvestre JS, Gross F, Grolleau JL, Saint-Lebese B, Peyrafitte JA, Fleury S, Gadelorge M, Taurand M, Dupuis-Coronas S, Leobon B, Casteilla L (2014) Phase I trial: the use of autologous cultured adipose-derived stroma/stem cells to treat patients with non-revascularizable critical limb ischemia. Cytotherapy 16(2):245–257CrossRefPubMedGoogle Scholar
  10. Cavanagh P, Attinger C, Abbas Z, Bal A, Rojas N, Xu ZR (2012) Cost of treating diabetic foot ulcers in five different countries. Diabetes Metab Res Rev 28(Suppl 1):107–111CrossRefPubMedGoogle Scholar
  11. Charles Brunicardi F, Andersen DK, Billiar TR, Dunn DL, Hunter JG, Matthews JB, Raphael E (2005). Pollock, Schwartz’s principles of surgery, Chapter 9. Wound healingGoogle Scholar
  12. De Francesco F, Graziano A, Trovato L, Ceccarelli G, Romano M, Marcarelli M, Cusella De Angelis GM, Cillo U, Riccio M, Ferraro GA (2016) A regenerative approach with dermal micrografts in the treatment of chronic ulcers. Stem Cell Rev 13(1):139–148Google Scholar
  13. Ding Y, Xu D, Feng G, Bushell A, Muschel RJ, Wood KJ (2009) Mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metalloproteinase-2 and -9. Diabetes 58:1797–1806CrossRefPubMedPubMedCentralGoogle Scholar
  14. Draper JS, Seguin CA, Andrews PW (2007) Phenotypic analyses of human embryonic stem cells. In: Sullivan S, Cowan CA, Eggan K (eds) Human embryonic stem cells: the practical handbook. Wiley, Cambridge, MA, pp 93–106Google Scholar
  15. Duque GA, Descoteaux A (2014) Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol 5:491Google Scholar
  16. Duscher D, Barrera J, Wong VW, Maan ZN, Whittam AJ, Januszyk M, Gurtner GC (2016) Stem cells in wound healing: the future of regenerative medicine? Mini-Rev Gerontol 62(2):216–225CrossRefGoogle Scholar
  17. Ertekin C, Taviloğlu K, Güloğlu R, Kurtoğlu M (2005) İstanbul Medikal Yayıncılık, İstanbul. Travma pp 488–501Google Scholar
  18. Fiorina P, Jurewicz M, Augello A et al (2009) Immunomodulatory function of bone marrow-derived mesenchymal stem cells in experimental autoimmune type 1 diabetes. J Immunol 183:993–1004CrossRefPubMedPubMedCentralGoogle Scholar
  19. Fritschi C (2001) Preventive care of the diabetic foot. Nurs Clin North Am 36:303–320PubMedGoogle Scholar
  20. Game FL, Hinchliffe RJ, Apelqvist J, Armstrong DG, Bakker K, Hartemann A, Löndahl M, Price PE, Jeffcoate WJ (2012) A systematic review of interventions to enhance the healing of chronic ulcers of the foot in diabetes. Diabetes Metab Res Rev 28(Suppl 1):119–141CrossRefPubMedGoogle Scholar
  21. Ghatak S, Maytin EV, Mack JA, Hascall VC, Atanelishvili I, Rodriguez RM, Markwald RR, Misra S (2015) Roles of proteoglycans and glycosaminoglycans in wound healing and fibrosis. Int J Cell Biol http://dx.doi.org/10.1155/2015/834893
  22. Ghieh F, Jurjus R, Ibrahim A, Geagea AG, Daouk H, El Baba B, Chams S, Matar M, Zein W, Jurjus A (2015) The use of stem cells in burn wound healing: a review. Biomed Res Int 2015:1–9CrossRefGoogle Scholar
  23. Gupta PK, Krishna M, Chullikana A, Desai S, Murugesan R, Dutta S, Sarkar U, Raju R, Dhar A, Parakh R, Jeyaseelan L, Viswanathan P, Vellotare PK, Seetharam RN, Thej C, Rengasamy M, Balasubramanian S, Majumdar AS (2016) Administration of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells in critical limb ischemia due to Buerger’s disease: phase II study report suggests clinical efficacy. Stem Cells Transl Med. pii: sctm.2016–0237Google Scholar
  24. Harrison NJ, Barbaric I, Andrews PW (2011) Human embryonic stem cell characterization: similarities and differences between cell lines and sources. In: Bongso A, Lee EH (eds) Stem cells: from bench to bedside, 2nd edn. World Scientific, Singapore, pp 1–22Google Scholar
  25. Jayaraman P, Nathan P, Vasanthan P, Musa S, Govindasamy V (2013) Stem cells conditioned medium: a new approach to skin wound healing management. Cell Biol Int 37(10):1122–1128CrossRefPubMedGoogle Scholar
  26. Jiang J, Lv Z, Gu Y, Li J, Xu L, Xu W et al (2010) Adult rat mesenchymal stem cells differentiate into neuronal-like phenotype and express a variety of neuro-regulatory molecules in vitro. Neurosci Res 66:46–52CrossRefPubMedGoogle Scholar
  27. Karnieli O, Izhar-Prato Y, Bulvik S, Efrat S (2007) Generation of insulin-producing cells from human bone marrow mesenchymal stem cells by genetic manipulation. Stem Cells 25:2837–2844CrossRefPubMedGoogle Scholar
  28. Khosrotehrani K (2013) Mesenchymal stem cell therapy in skin: why and what for? Exp Dermatol 22(5):307–310CrossRefPubMedGoogle Scholar
  29. Lau TW, Lam FF, Lau KM, Chan YW, Lee KM, Sahota DS et al (2009) Pharmacological investigation on the wound healing effects of Radix Rehmanniae in an animal model of diabetic foot ulcer. J Ethnopharmacol 123:155–162CrossRefPubMedGoogle Scholar
  30. Lee HC, An SG, Lee HW, Park JS, Cha KS, Hong TJ, Park JH, Lee SY, Kim SP, Kim YD, Chung SW, Bae YC, Shin YB, Kim JI, Jung JS (2012) Safety and effect of adipose tissue-derived stem cell implantation in patients with critical limb ischemia: a pilot study. Circ J 76(7):1750–1760. Epub 2012 Apr 12CrossRefPubMedGoogle Scholar
  31. Lee DE, Ayoub N, Agrawal DK (2016) Mesenchymal stem cells and cutaneous wound healing: novel methods to increase cell delivery and therapeutic efficacy. Stem Cell Res Ther 7:37CrossRefPubMedPubMedCentralGoogle Scholar
  32. Leirósa GJ, Kusinskya AG, Dragob H, Bossib S, Sturlab F, Castellanosa FL, Stellac IY, Balañáa ME (2014) Dermal papilla cells improve the wound healing process and generate hair Bud-like structures in grafted skin substitutes using hair follicle stem cells. Stem Cells Trans Med 3(10):1209–1219CrossRefGoogle Scholar
  33. Leung PC (2007) Diabetic foot ulcers – a comprehensive review. Surgeon 5(4):219–231CrossRefPubMedGoogle Scholar
  34. Li XY, Zheng ZH, Li XY, Guo J, Zhang Y, Li H, Wang YW, Ren J, Wu ZB (2013) Treatment of foot disease in patients with type 2 diabetes mellitus using human umbilical cord blood mesenchymal stem cells: response and correction of immunological anomalies. Curr Pharm Des 19(27):4893–4899CrossRefPubMedGoogle Scholar
  35. Li XY, Zheng ZH, Guo J, Zhang Y, Li H, Wang YW, Ren J, Wu ZB (2014) Treatment of foot disease in patients with type 2 diabetes mellitus using human umbilical cord blood mesenchymal stem cells: response and correction of immunological anomalies. Curr Pharm Des 19(27):4893–4899CrossRefGoogle Scholar
  36. Lu D, Chen B, Liang Z, Deng W, Jiang Y, Li S, Xu J, Wu Q, Zhang Z, Xie B, Chen S (2011a) Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial. Diabetes Res Clin Pract 92(1):26–36CrossRefPubMedGoogle Scholar
  37. Madec AM, Mallone R, Afonso G et al (2009) Mesenchymal stem cells protect NOD mice from diabetes by inducing regulatory T cells. Diabetologia 52:1391–1399CrossRefPubMedGoogle Scholar
  38. Maehr R, Chen S, Snitow M, Ludwig T, Yagasaki L, Goland R, Leibel RL, Melton DA (2009) Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci U S A 106:15768–15773CrossRefPubMedPubMedCentralGoogle Scholar
  39. Marieb EN (1995) Human anatomy and physiology. Hodder & Stoughton, London, p 103Google Scholar
  40. Melton DA, Cowan C (2009) “Stemness”: definitions, criteria and standards. In: Lanza R, Gaerhart J, Hogan B, Melton D, Thomson J, Wilmut I (eds) Essentials of stem cell biology, 2nd edn. Academic Press, San Diego, pp 23–29Google Scholar
  41. Metcalfe AD, Ferguson MWJ (2007) Tissue engineering of replacement skin: the crossroads of biomaterials, wound healing, embryonic development, stem cells and regeneration. J R Soc Interface 4(14):413–437CrossRefPubMedGoogle Scholar
  42. Morigi M, Imberti B, Zoja C, Corna D, Tomasoni S, Abbate M et al (2004) Mesenchymal stem cells are renotropic, helping to repair the kidney and improve function in acute renal failure. J Am Soc Nephrol 15:1794–1804CrossRefPubMedGoogle Scholar
  43. Nandy D, Mukhopadhyay D (2011) Growth factor mediated signaling in pancreatic pathogenesis. Cancers Basel 3(1):841–871CrossRefPubMedPubMedCentralGoogle Scholar
  44. Norton JA, Bollinger RR, Chang AE, Lowry SF, Mulvihill SJ, Pass HI, Thompson RW (2003) Essential practice of surgery: basic science and clinical evidence. In: Lorenz HP, Longaker MT (eds) Chapter 7: Wounds: biology, pathology and management. Springer, New York, pp 89–94Google Scholar
  45. Oskouei BN et al (2012) Increased potency of cardiac stem cells compared with bone marrow mesenchymal stem cells in cardiac repair. Stem Cells Transl Med 1(2):116–124CrossRefPubMedPubMedCentralGoogle Scholar
  46. Ozturk S, Karagoz H (2015) Experimental stem cell therapies on burn wound: do source, dose, timing and method matter? Burns 41:1133CrossRefPubMedGoogle Scholar
  47. Pawlina W Histology: a text and atlas: with correlated cell and molecular biology. 7th Ed. . Philadelphia Wolters Kluwer. China. Int. Ed. 2016. p. 488–516.Google Scholar
  48. Paz JC, West MP. (2014) Acute care handbook for phsical therapists, 4th edn. Saunders, Philadelphia, pp 297–299.Google Scholar
  49. Polo JM, Liu S, Figueroa MA, Kulalert W, Eminli S, Tan KY, Apostolou E, Stadtfeld M, Li Y, Shioda T, Natesan S, Wagers AJ, Melnick A, Evans T, Hochedlinger K (2010) Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nat Biotechnol 28:848–855CrossRefPubMedPubMedCentralGoogle Scholar
  50. Reed MJ, Meszaros K, Entes LJ, Claypool MD, Pinkett JG, Gadbois TM et al (2000) A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. Metabolism 49:1390–1394CrossRefPubMedGoogle Scholar
  51. Sener LT, Albeniz I (2015) Challenge of mesenchymal stem cells against diabetic foot ulcer. Curr Stem Cell Res Ther 10:530–534CrossRefPubMedGoogle Scholar
  52. Shabbir A, Cox A, Rodriguez-Menocal L, Salgado M, Van Badiavas E (2015) Mesenchymal stem cell exosomes induce proliferation and migration of normal and chronic wound fibroblasts, and enhance angiogenesis in vitro. Stem Cells Dev 24(14):1635–1647CrossRefPubMedPubMedCentralGoogle Scholar
  53. Shumakov VI, Onishchenko NA, Rasulov MF, Krasheninnikov ME, Zaidenov VA (2003) Mesenchymal bone marrow stem cells more effectively stimulate regeneration of deep burn wounds than embryonic fibroblasts. Bull Exp Biol Med 136(2):192–195CrossRefPubMedGoogle Scholar
  54. Singer DD, Singer AJ, Gordon C, Brink P (2013) The effects of rat mesenchymal stem cells on injury progression in a rat model. Acad Emerg Med 20(4):398–402CrossRefPubMedGoogle Scholar
  55. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676CrossRefPubMedGoogle Scholar
  56. Vaccari DA, Strom PF, Alleman JE (2005) Environmental biology for engineers and scientists. Wiley-Interscience, HobokenCrossRefGoogle Scholar
  57. Van Koppen CJ, Hartmann RW (2015) Advances in the treatment of chronic wounds: a patent review. Expert Opin Ther Pat 25(8):931–937CrossRefPubMedGoogle Scholar
  58. van Zuijlen PPM, Gardien KLM, Jaspers MEH, Bos EJ, Baas DC, van Trier AJM, Middelkoop E (2015) Tissue engineering in burn scar reconstruction. Burns Trauma 3:18CrossRefPubMedPubMedCentralGoogle Scholar
  59. Jeffrey Weinzweig (1999) Plastic surgery secrets. Hanley & Belfus Inc. 156053219X, 9781560532194Google Scholar
  60. Xue M, Jackson CJ (2015) Extracellular matrix reorganization during wound healing and its impact on abnormal scarring. Adv Wound Care (New Rochelle) 4(3):119–136CrossRefGoogle Scholar
  61. Xue L, Xu YB, Xie JL, Tang JM, Shu B, Chen L, Qi SH, Liu XS (2013) Effects of human bone marrow mesenchymal stem cells on burn injury healing in a mouse model. Int J Clin Exp Pathol 6(7):1327–1336PubMedPubMedCentralGoogle Scholar
  62. Yazdanpanah L, Nasiri M, Adarvishi S (2015) Literature review on the management of diabetic foot ulcer. World J Diabetes 6(1):37–53CrossRefPubMedPubMedCentralGoogle Scholar
  63. Yolanda MM, Maria AV, Amaia FG, Marcos PB, Silvia PL et al (2014) Adult stem cell therapy in chronic wound healing. J Stem Cell Res Ther 4:162CrossRefGoogle Scholar
  64. Zhang J, Guan J, Niu X, Hu G, Guo S, Li Q, Xie Z, Zhang C, Wang Y (2015a) Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. J Transl Med 13:49CrossRefPubMedPubMedCentralGoogle Scholar
  65. Zhang B, Wang M, Gong A, Zhang X, Wu X, Zhu Y, Shi H, Wu L, Zhu W, Qian H, Xu W (2015b) HucMSC-exosome mediated-Wnt4 signaling is required for cutaneous wound healing. Stem Cells 33:2158–2168CrossRefPubMedGoogle Scholar
  66. Zhao QS, Xia N, Zhao N, Li M, Bi CL, Zhu Q, Qiao GF, Cheng ZF (2014) Localization of human mesenchymal stem cells from umbilical cord blood and their role in repair of diabetic foot ulcer in rat. Int J Biol Sci 10(1):80–89CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Leyla Türker Şener
    • 1
  • Hakan Darici
    • 2
  • Işil Albeniz
    • 1
  • Erdal Karaöz
    • 2
  1. 1.Department of BiophysicsIstanbul University, Istanbul Faculty of MedicineCapa-IstanbulTurkey
  2. 2.Department of Histology and EmbryologyIstinye University Hospital, Faculty of MedicineTopkapı-IstanbulTurkey

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