Volume 16, Issue 1 (Winter & Spring 2019)                   ASJ 2019, 16(1): 1-12 | Back to browse issues page

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Heidari F, Nobakht M, Shams A, Yari A. Application of Hair Follicle Bulge Stem Cells in Wound Healing. ASJ 2019; 16 (1) :1-12
URL: http://anatomyjournal.ir/article-1-210-en.html
1- Department of Anatomy, School of Medicine, Qom University of Medical Sciences, Qom, Iran.
2- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
3- Department of Anatomy, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
Abstract:   (4989 Views)
Despite the significant advances in regenerative medicine, wound healing has remained a challenging clinical problem. Skin is the largest human organ with many vital functions; therefore, any damage to its normal structure should be treated as soon as possible. Easy access to skin stem cells has created a lot of excitement in therapeutic applications. “Cell therapy” is considered a novel method in regenerative medicine, especially when conventional treatments fail. Candidate cell populations for therapeutic applications include embryonic, induced pluripotent, adult mesenchymal, and hair follicle stem cells. It is possible to differentiate stem cells separated from the bulge area of hair follicle into neurons, melanocytes, keratinocytes, glia and smooth muscle cells that are negative for the keratinocyte marker kr15. 
This review discusses the plasticity of skin stem cells, especially stem cells located in the hair follicle and their involvement in wound healing, gene expression profile in wound healing, hair follicle stem cells, and their surrounding epidermis. Moreover, the ability of hair follicle stem cells for treating wounds and regenerative medicine is going to be discussed. Eventually we suggest the hair follicle as an ideal source of stem cells for cell therapy and regenerative medicine because they are abundant with easy access and great differentiation ability.
Full-Text [PDF 731 kb]   (1734 Downloads) |   |   Full-Text (HTML)  (2144 Views)  
Type of Study: Review | Subject: Stem Cell
Received: 2018/02/10 | Accepted: 2018/08/25 | Published: 2019/01/1

1. Smith MA, Dahlen NR. Clinical practice guideline surgical site infection prevention. Orthopedic Nursing. 2013; 32(5):242-8. [DOI:10.1097/NOR.0b013e3182a39c6b] [DOI:10.1097/NOR.0b013e3182a39c6b]
2. Smith RL, Bohl JK, McElearney ST, Friel CM, Barclay MM, Sawyer RG, et al. Wound infection after elective colorectal resection. Annals of Surgery. 2004; 239(5):599-605. [DOI:10.1097/01.sla.0000124292.21605.99] [PMID] [PMCID]
3. Natarajan S, Williamson D, Stiltz AJ, Harding K. Advances in wound care and healing technology. American Journal of Clinical Dermatology. 2000; 1(5):269-75. [DOI:10.2165/00128071-200001050-00002] [PMID] [DOI:10.2165/00128071-200001050-00002]
4. Hanson SE, Bentz ML, Hematti P. Mesenchymal stem cell therapy for nonhealing cutaneous wounds. Plastic and Reconstructive Surgery. 2010; 125(2):510-6. [DOI:10.1097/PRS.0b013e3181c722bb] [PMID] [PMCID] [DOI:10.1097/PRS.0b013e3181c722bb]
5. Lazic T, Falanga V. Bioengineered skin constructs and their use in wound healing. Plastic and Reconstructive Surgery. 2011; 127, 75S-90S. [DOI:10.1097/PRS.0b013e3182009d9f] [PMID] [DOI:10.1097/PRS.0b013e3182009d9f]
6. Lazarus GS, Cooper DM, Knighton DR, Percoraro RE, Rodeheaver G, Robson MC. Definitions and guidelines for assessment of wounds and evaluation of healing. Wound Repair and Regeneration. 1994; 2(3):165-70. [DOI:10.1046/j.1524-475X.1994.20305.x] [PMID]
7. de Laat EH, van den Boogaard MH, Spauwen PH, van Kuppevelt DH, van Goor H, Schoonhoven L. Faster wound healing with topical negative pressure therapy in difficult-to-heal wounds: a prospective randomized controlled trial. Annals of Plastic Surgery. 2011; 67(6):626-31. [DOI:10.1097/SAP.0b013e31820b3ac1] [PMID] [DOI:10.1097/SAP.0b013e31820b3ac1]
8. Lutz NW, Confort Gouny S, Casanova D, Andrac Meyer L, Magalon G, Cozzone PJ. Conditions of wound healing and cutaneous growth affect metabolic performance of skin following plastic surgery. Wound Repair and Regeneration. 2007; 15(4):491-6. [DOI:10.1111/j.1524-475X.2007.00268.x] [PMID]
9. Teng M, Huang Y, Zhang H. Application of stems cells in wound healing-an update. Wound Repair and Regeneration. 2014; 22(2):151-60. [DOI:10.1111/wrr.12152] [PMID]
10. Velnar T, Bailey T, Smrkolj V. The wound healing process: An overview of the cellular and molecular mechanisms. The Journal of International Medical Research. 2009; 37(5):1528-42. [DOI:10.1177/147323000903700531] [PMID] [DOI:10.1177/147323000903700531]
11. Chodorowska G, Rogus Skorupska D. Cutaneous wound healing. Annales Universitatis Mariae Curie-Sklodowska. 2004; 59(2):403-7. [PMID] [PMID]
12. Cherubino M, Rubin JP, Miljkovic N, Kelmendi Doko A, Marra KG. Adipose-derived stem cells for wound healing applications. Annals of Plastic Surgery. 2011; 66(2):210-5. [DOI:10.1097/SAP.0b013e3181e6d06c] [PMID] [DOI:10.1097/SAP.0b013e3181e6d06c]
13. Ristow HJ. Studies on stimulation of DNA synthesis with epidermal growth factor and insulin-like growth factor-I in cultured human keratinocytes. Growth Regulation. 1996; 6(2):96-109. [PMID] [PMID]
14. Kwon YB, Kim HW, Roh DH, Yoon SY, Baek RM, Kim JY, et al. Topical application of epidermal growth factor accelerates wound healing by myofibroblast proliferation and collagen synthesis in rat. Journal of Veterinary Science. 2006; 7(2):105-9. [DOI:10.4142/jvs.2006.7.2.105] [PMID] [PMCID] [DOI:10.4142/jvs.2006.7.2.105]
15. Bhora FY, Dunkin BJ, Batzri S, Aly HM, Bass BL, Sidawy AN, et al. Effect of growth factors on cell proliferation and epithelialization in human skin. The Journal of Surgical Research. 1995; 59(2):236-44. [DOI:10.1006/jsre.1995.1160] [PMID] [DOI:10.1006/jsre.1995.1160]
16. Kamalati T, Howard M, Brooks RF. IGF I induces differentiation in a transformed human keratinocyte line. Journal of Biological Chemistry. 1989; 106(2):283-93. [PMID]
17. Shirakata Y, Komurasaki T, Toyoda H, Hanakawa Y, Yamasaki k, Tokumaru Sh et al. Epiregulin, a novel member of the epidermal growth factor family, is an autocrine growth factor in normal human keratinocytes. The Journal of Biological Chemistry. 2000; 275(8):5748-53. [DOI:10.1074/jbc.275.8.5748] [PMID] [DOI:10.1074/jbc.275.8.5748]
18. Song YH, Zhu YT, Ding J, Zhou FY, Xue JX, Jung JH, et al. Distribution of fibroblast growth factors and their roles in skin fibroblast cell migration. Molecular Medicine Reports. 2016; 14(4):3336-42. [DOI:10.3892/mmr.2016.5646] [DOI:10.3892/mmr.2016.5646]
19. Wang G, Higgins PJ, Gannon M, Staiano Coico L. Transforming growth factor-beta 1 acts cooperatively with sodium n-butyrate to induce differentiation of normal human keratinocytes. Experimental Cell Research. 1992; 198(1):27-30. [DOI:10.1016/0014-4827(92)90144-W] [DOI:10.1016/0014-4827(92)90144-W]
20. Chomiski V, Gragnani A, Bonucci J, Correa SA, Noronha SM, Ferreira LM. Keratinocyte growth factor and the expression of wound-healing-related genes in primary human keratinocytes from burn patients. Acta Cirurgica Brasileira. 2016; 31(8):505-12. [DOI:10.1590/S0102-865020160080000002] [PMID]
21. Grabbe J, Welker P, Rosenbach T, Nürnberg W, Krüger Krasagakes S, Artuc M, et al. Release of stem cell factor from a human keratinocyte line, HaCaT, is increased in differentiating versus proliferating cells. The Journal of Investigative Dermatology. 1996; 107(2):219-24. [DOI:10.1111/1523-1747.ep12329664] [PMID] [DOI:10.1111/1523-1747.ep12329664]
22. D'Souza SJ, Pajak A, Balazsi K, Dagnino L. Ca2+ and BMP-6 signaling regulate E2F during epidermal keratinocyte differentiation. The Journal of Biological Chemistry. 2001; 276(26):23531-8. [DOI:10.1074/jbc.M100780200] [PMID] [DOI:10.1074/jbc.M100780200]
23. Oike Y, Yasunaga K, Ito Y, Matsumoto SI, Maekawa H, Morisada T, et al. Angiopoietin-related Growth Factor (AGF) promotes epidermal proliferation, remodeling, and regeneration. Proceedings of the National Academy of Sciences of the United States of America. 2003; 100(16):9494-9. [DOI:10.1073/pnas.1531901100] [PMID] [PMCID] [DOI:10.1073/pnas.1531901100]
24. Kim DS, Korting HC, Schafer Korting M. Effects of growth factors on the proliferation of human keratinocytes and fibroblasts in vitro. Die Pharmazie. 1998; 53(1):51-7. [PMID] [PMID]
25. Braunstein S, Kaplan G, Gottlieb AB, Schwartz, M., Walsh, G., Abalos, R.M., et al. GM-CSF activates regenerative epidermal growth and stimulates keratinocyte proliferation in human skin in vivo. The Journal of Investigative Dermatology. 1994; 103(4):601-4. [DOI:10.1111/1523-1747.ep12396936] [PMID] [DOI:10.1111/1523-1747.ep12396936]
26. Bikle DD, Pillai S, Gee E, Hincenbergs M. Tumor necrosis factor-alpha regulation of 1, 25-dihydroxyvitamin D production by human keratinocytes. Endocrinology. 1991; 129(1):33-8. [DOI:10.1210/endo-129-1-33] [PMID] [DOI:10.1210/endo-129-1-33]
27. Maas Szabowski N, Stark HJ, Fusenig NE. Keratinocyte growth regulation in defined organotypic cultures through IL-1-induced keratinocyte growth factor expression in resting fibroblasts. The Journal of Investigative Dermatology. 2000; 114(6):1075-84. [DOI:10.1046/j.1523-1747.2000.00987.x] [PMID] [DOI:10.1046/j.1523-1747.2000.00987.x]
28. Al Refu K, Edward S, Ingham E, Goodfield M. Expression of hair follicle stem cells detected by cytokeratin 15 stain: Implications for pathogenesis of the scarring process in cutaneous lupus erythematosus. The British Journal of Dermatology. 2009; 160(6):1188-96. [DOI:10.1111/j.1365-2133.2009.09074.x] [PMID] [DOI:10.1111/j.1365-2133.2009.09074.x]
29. Di Marco E, Mathor M, Bondanza S, Cutuli N, Marchisio PC, Cancedda R, et al. Nerve growth factor binds to normal human keratinocytes through high and low affinity receptors and stimulates their growth by a novel autocrine loop. The Journal Of Biological Chemistry. 1993; 268(30):22838-46. [PMID] [PMID]
30. Darkazalli A, Ismail AA, Abad N, Grant SC, Levenson CW. Use of human mesenchymal stem cell treatment to prevent anhedonia in a rat model of traumatic brain injury. Restorative Neurology and Neuroscience. 2016; 34(3):433-41. [DOI:10.3233/RNN-150628] [PMID] [DOI:10.3233/RNN-150628]
31. Garcia Gomez I, Elvira G, Zapata AG, Lamana ML, Ramírez M, García Castro J, et al. Mesenchymal stem cells: biological properties and clinical applications. Expert Opinion on Biological Therapy. 2010; 10(10):1453-68. [DOI:10.1517/14712598.2010.519333] [PMID] [DOI:10.1517/14712598.2010.519333]
32. Watt FM, Hogan BL. Out of eden: Stem cells and their niches. Science. 2000; 287(5457):1427-30. [DOI:10.1126/science.287.5457.1427] [PMID] [DOI:10.1126/science.287.5457.1427]
33. Weissman IL. Stem cells: Units of development, units of regeneration, and units in evolution. Cell. 2000; 100(1):157-68. [DOI:10.1016/S0092-8674(00)81692-X] [DOI:10.1016/S0092-8674(00)81692-X]
34. Friedenstein AJ, Piatetzky-Shapiro II, Petrakova KV. Osteogenesis in transplants of bone marrow cells. Journal of Embryology and Experimental Morphology. 1966; 16(3):381-390. [PMID] [PMID]
35. Levy YS, Stroomza M, Melamed E, Offen D. Embryonic and adult stem cells as a source for cell therapy in Parkinson's disease. Journal of Molecular Neuroscience. 2004; 24(3):353-86. [DOI:10.1385/JMN:24:3:353] [DOI:10.1385/JMN:24:3:353]
36. Amoh Y, Li L, Campillo R, Kawahara K, Katsuoka K, Penman S, et al. Implanted hair follicle stem cells form Schwann cells that support repair of severed peripheral nerves. Proceedings of the National Academy of Sciences of the United States of America. 2005; 102(49):17734-8. [DOI:10.1073/pnas.0508440102] [PMID] [PMCID] [DOI:10.1073/pnas.0508440102]
37. Barry FP, Murphy JM. Mesenchymal stem cells: Clinical applications and biological characterization. The International Journal of Biochemistry & Cell Biology. 2004; 36(4):568-84. [DOI:10.1016/j.biocel.2003.11.001] [PMID] [DOI:10.1016/j.biocel.2003.11.001]
38. Gerecht Nir S, Itskovitz Eldor J. Cell therapy using human embryonic stem cells. Transplant Immunology. 2004; 12(3-4):203-9. [DOI:10.1016/j.trim.2003.12.013] [PMID] [DOI:10.1016/j.trim.2003.12.013]
39. Gerlach JC, Zeilinger K. Adult stem cell technology-prospects for cell based therapy in regenerative medicine. The International Journal of Artificial Organs. 2002; 25(2):83-90. [DOI:10.1177/039139880202500202] [PMID] [DOI:10.1177/039139880202500202]
40. Neuss S, Becher E, Woltje M, Tietze L, Jahnen Dechent W. Functional expression of HGF and HGF receptor/c-met in adult human mesenchymal stem cells suggests a role in cell mobilization, tissue repair, and wound healing. Stem Cells. 2004; 22(3):405-14. [DOI:10.1634/stemcells.22-3-405] [PMID] [DOI:10.1634/stemcells.22-3-405]
41. Strioga M, Viswanathan S, Darinskas A, Slaby O, Michalek J. Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells and Development. 2012; 21(14):2724-52. [DOI:10.1089/scd.2011.0722] [PMID] [DOI:10.1089/scd.2011.0722]
42. Jahoda CA, Reynolds AJ. Hair follicle dermal sheath cells: Unsung participants in wound healing. Lancet. 2001; 358(9291):1445-8. [DOI:10.1016/S0140-6736(01)06532-1] [DOI:10.1016/S0140-6736(01)06532-1]
43. Gharzi A, Reynolds AJ, Jahoda CA. Plasticity of hair follicle dermal cells in wound healing and induction. Experimental Dermatology. 2003; 12(2):126-136. [DOI:10.1034/j.1600-0625.2003.00106.x] [PMID] [DOI:10.1034/j.1600-0625.2003.00106.x]
44. Morasso MI, Tomic Canic M. Epidermal stem cells: The cradle of epidermal determination, differentiation and wound healing. Biology of the Cell. 2005; 97(3):173-83. [DOI:10.1042/BC20040098] [PMID] [PMCID] [DOI:10.1042/BC20040098]
45. Brouard M, Barrandon Y. Controlling skin morphogenesis: hope and despair. Current Opinion in Biotechnology. 2003; 14(5):520-5. [DOI:10.1016/j.copbio.2003.09.005] [PMID] [DOI:10.1016/j.copbio.2003.09.005]
46. Hoffman RM. The pluripotency of hair follicle stem cells. Cell Cycle. 2006; 5(3):232-3. [DOI:10.4161/cc.5.3.2397] [PMID] [DOI:10.4161/cc.5.3.2397]
47. Morris RJ, Liu Y, Marles L, Yang Z, Trempus C, Li S, et al. Capturing and profiling adult hair follicle stem cells. Nature Biotechnology. 2004; 22(4):411-7. [DOI:10.1038/nbt950] [PMID] [DOI:10.1038/nbt950]
48. Levy V, Lindon C, Zheng Y, Harfe BD, Morgan BA. Epidermal stem cells arise from the hair follicle after wounding. The FASEB Journal. 2007; 21(7):1358-66. [DOI:10.1096/fj.06-6926com] [PMID] [DOI:10.1096/fj.06-6926com]
49. Lako M, Armstrong L, Cairns PM, Harris S, Hole N, Jahoda CA. Hair follicle dermal cells repopulate the mouse haematopoietic system. Journal of Cell Science. 2002; 115(20):3967-74. [DOI:10.1242/jcs.00060] [PMID] [DOI:10.1242/jcs.00060]
50. Shi C, Mai Y, Cheng T. Identification of hematopoietic cell populations from the dermal papillae of human hair follicles. Transplantation Proceedings. 2004; 36(10):3208-11. [DOI:10.1016/j.transproceed.2004.11.104] [PMID] [DOI:10.1016/j.transproceed.2004.11.104]
51. Toma JG, McKenzie IA, Bagli D, Miller FD. Isolation and characterization of multipotent skin-derived precursors from human skin. Stem cells. 2005; 23(6):727-37. [DOI:10.1634/stemcells.2004-0134] [PMID]
52. Steingrimsson E, Copeland NG, Jenkins NA. Melanocyte stem cell maintenance and hair graying. Cell. 2005; 121(1):9-12. [DOI:10.1016/j.cell.2005.03.021] [PMID]
53. Young HE, Steele TA, Bray RA, Hudson J, Floyd JA, Hawkins K, et al. Human reserve pluripotent mesenchymal stem cells are present in the connective tissues of skeletal muscle and dermis derived from fetal, adult, and geriatric donors. The Anatomical Record. 2001; 264(1):51-62. [DOI:10.1002/ar.1128] [PMID] [DOI:10.1002/ar.1128]
54. Badiavas EV, Abedi M, Butmarc J, Falanga V, Quesenberry P. Participation of bone marrow derived cells in cutaneous wound healing. Journal of Cellular Physiology. 2003; 196(2):245-250. [DOI:10.1002/jcp.10260] [PMID] [DOI:10.1002/jcp.10260]
55. Falanga V, Iwamoto S, Chartier M, Hudson J, Floyd JA, Hawkins K, et al. Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds. Tissue Engineering. 2007; 13(6):1299-1312. [DOI:10.1089/ten.2006.0278] [PMID] [DOI:10.1089/ten.2006.0278]
56. Yoshikawa T, Mitsuno H, Nonaka I, Sen Y, Kawanishi K, Inada Y, et al. Wound therapy by marrow mesenchymal cell transplantation. Plastic and Reconstructive Surgery. 2008; 121(3):860-77. [DOI:10.1097/01.prs.0000299922.96006.24] [PMID] [DOI:10.1097/01.prs.0000299922.96006.24]
57. 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 Research. 2009; 12(5):359-66. [DOI:10.1089/rej.2009.0872] [PMID] [DOI:10.1089/rej.2009.0872]
58. Lee HC, An SG, Lee HW, Park JS, Cha KS, Hong TJ, et al. Safety and effect of adipose tissue-derived stem cell implantation in patients with critical limb ischemia: A pilot study. Circulation Journal. 2012; 76(7):1750-60. [DOI:10.1253/circj.CJ-11-1135] [PMID] [DOI:10.1253/circj.CJ-11-1135]
59. Amini N, Vousooghi N, Hadjighassem M, Bakhtiyari M, Mousavi N, Safakheil H, et al. Efficacy of human adipose tissue-derived stem cells on neonatal bilirubin encephalopathy in rats. Neurotoxicity Research. 2016; 29(4):514-24. [DOI:10.1007/s12640-016-9599-3] [PMID] [DOI:10.1007/s12640-016-9599-3]
60. Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circulation Research. 1999; 85(3):221-8. [DOI:10.1161/01.RES.85.3.221] [PMID] [DOI:10.1161/01.RES.85.3.221]
61. 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. [DOI:10.1016/S0140-6736(09)61496-3] [DOI:10.1016/S0140-6736(09)61496-3]
62. Yang R, Zheng Y, Burrows M, Liu S, Wei Z, Nace A, et al. Generation of folliculogenic human epithelial stem cells from induced pluripotent stem cells. Nature Communications. 2014; 5:3071. [DOI:10.1038/ncomms4071] [PMID] [PMCID] [DOI:10.1038/ncomms4071]
63. 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(10):e77673. [DOI:10.1371/journal.pone.0077673] [PMID] [PMCID] [DOI:10.1371/journal.pone.0077673]
64. 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. Science Translational Medicine. 2014; 6(264):264ra163. [DOI:10.1126/scitranslmed.3009540] [PMID] [PMCID] [DOI:10.1126/scitranslmed.3009540]
65. Martin P, Leibovich SJ. Inflammatory cells during wound repair: The good, the bad and the ugly. Trends in Cell Biology. 2005; 15(11):599-607. [DOI:10.1016/j.tcb.2005.09.002] [PMID] [DOI:10.1016/j.tcb.2005.09.002]
66. 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. [DOI:10.1016/j.cell.2006.07.024] [PMID] [DOI:10.1016/j.cell.2006.07.024]
67. Odorico JS, Kaufman DS, Thomson JA. Multilineage differentiation from human embryonic stem cell lines. Stem Cells. 2001; 19(3):193-204. [DOI [DOI:10.1634/stemcells.19-3-193] [PMID]

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