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Advances in Hair Restoration

  • FACIAL PLASTICS: Facial Skin Rejuvenation (PJ Carniol and AE Brissett, Section Editors)
  • Published:
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Abstract

Purpose of Review

Treatment for alopecia remains limited in terms of medication side effect profile, patient adherence to treatment, and clinical response. We sought to review the literature for burgeoning therapies affecting hair growth through regulation of paracrine signaling and its effect on dermal papilla cells.

Recent Findings

Newly proposed treatments for alopecia, including stem cell therapy derived from adipose tissue, hair follicles, umbilical cord blood, or bone marrow, and extracellular vesicles, such as exosomes, are tied to hair follicle regulation and regeneration through paracrine factor signaling, specifically through the Wnt/β-catenin signaling pathway.

Summary

Recent advances in hair follicle regeneration and regulation, including stem cell therapy or treatment with exosomes, modulate alopecia through dermal papilla cell regulation and promoting hair follicle growth through anagen phase induction. Randomized, high-quality studies are needed to determine safety, efficacy, and appropriate treatment protocols using these newest therapies.

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References

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

  1. Global Alopecia Market is Forecast to Deliver a CAGR of 5.1% Between 2019 and 2027. Available at: https://www.globenewswire.com/en/news-release/2020/12/09/2142566/28124/en/Global-Alopecia-Market-is-Forecast-to-Deliver-a-CAGR-of-5-1-Between-2019-and-2027.html. Accessed June 15 2021.

  2. Androgenetic alopecia. Available at: https://medlineplus.gov/genetics/condition/androgenetic-alopecia/#frequency. Accessed June 15 2021.

  3. Garza LA, Yang CC, Zhao T, et al. Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells. J Clin Invest. 2011;121:613–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Avci P, Gupta GK, Clark J, Wikonkal N, Hamblin MR. Low-level laser (light) therapy (LLLT) for treatment of hair loss. Lasers Surg Med. 2014;46:144–51.

    Article  PubMed  Google Scholar 

  5. Gupta AK, Mays RR, Dotzert MS, Versteeg SG, Shear NH, Piguet V. Efficacy of non-surgical treatments for androgenetic alopecia: a systematic review and network meta-analysis. J Eur Acad Dermatol Venereol. 2018;32:2112–25.

    Article  CAS  PubMed  Google Scholar 

  6. Mounsey AL, Reed SW. Diagnosing and treating hair loss. Am Fam Physician. 2009;80:356–62.

    PubMed  Google Scholar 

  7. Dey-Rao R, Sinha AA. Genome-wide gene expression dataset used to identify potential therapeutic targets in androgenetic alopecia. Data Brief. 2017;13:85–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. •• Choi BY. Targeting Wnt/beta-catenin Pathway for developing therapies for hair loss. Int J Mol Sci 2020;21. Important article summarizing the importance of Wnt/beta-catenin signaling in hair loss.

  9. Ito M, Yang Z, Andl T, et al. Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature. 2007;447:316–20.

    Article  CAS  PubMed  Google Scholar 

  10. Huelsken J, Vogel R, Erdmann B, Cotsarelis G, Birchmeier W. beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell. 2001;105:533–45.

    Article  CAS  PubMed  Google Scholar 

  11. Andl T, Reddy ST, Gaddapara T, Millar SE. WNT signals are required for the initiation of hair follicle development. Dev Cell. 2002;2:643–53.

    Article  CAS  PubMed  Google Scholar 

  12. Van Mater D, Kolligs FT, Dlugosz AA, Fearon ER. Transient activation of beta -catenin signaling in cutaneous keratinocytes is sufficient to trigger the active growth phase of the hair cycle in mice. Genes Dev. 2003;17:1219–24.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Li J, Ji L, Chen J, Zhang W, Ye Z. Wnt/beta-catenin signaling pathway in skin carcinogenesis and therapy. Biomed Res Int 2015;2015:964842.

  14. Reddy S, Andl T, Bagasra A, et al. Characterization of Wnt gene expression in developing and postnatal hair follicles and identification of Wnt5a as a target of Sonic hedgehog in hair follicle morphogenesis. Mech Dev. 2001;107:69–82.

    Article  CAS  PubMed  Google Scholar 

  15. • Yuan AR, Bian Q, Gao JQ. Current advances in stem cell-based therapies for hair regeneration. Eur J Pharmacol 2020;881:173197. Summary of stem cell-based therapies in the treatment of alopecia.

  16. Kishimoto J, Burgeson RE, Morgan BA. Wnt signaling maintains the hair-inducing activity of the dermal papilla. Genes Dev. 2000;14:1181–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Li YH, Zhang K, Yang K, et al. Adenovirus-mediated Wnt10b overexpression induces hair follicle regeneration. J Invest Dermatol. 2013;133:42–8.

    Article  CAS  PubMed  Google Scholar 

  18. Li YH, Zhang K, Ye JX, Lian XH, Yang T. Wnt10b promotes growth of hair follicles via a canonical Wnt signalling pathway. Clin Exp Dermatol. 2011;36:534–40.

    Article  PubMed  Google Scholar 

  19. Dong L, Hao H, Xia L, et al. Treatment of MSCs with Wnt1a-conditioned medium activates DP cells and promotes hair follicle regrowth. Sci Rep. 2014;4:5432.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Ohnemus U, Uenalan M, Conrad F, et al. Hair cycle control by estrogens: catagen induction via estrogen receptor (ER)-alpha is checked by ER beta signaling. Endocrinology. 2005;146:1214–25.

    Article  CAS  PubMed  Google Scholar 

  21. Narhi K, Jarvinen E, Birchmeier W, Taketo MM, Mikkola ML, Thesleff I. Sustained epithelial beta-catenin activity induces precocious hair development but disrupts hair follicle down-growth and hair shaft formation. Development. 2008;135:1019–28.

    Article  CAS  PubMed  Google Scholar 

  22. Lo Celso C, Prowse DM, Watt FM. Transient activation of beta-catenin signalling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours. Development. 2004;131:1787–99.

    Article  CAS  PubMed  Google Scholar 

  23. Gat U, DasGupta R, Degenstein L, Fuchs E. De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Cell. 1998;95:605–14.

    Article  CAS  PubMed  Google Scholar 

  24. Xiong Y, Liu Y, Song Z, Hao F, Yang X. Identification of Wnt/beta-catenin signaling pathway in dermal papilla cells of human scalp hair follicles: TCF4 regulates the proliferation and secretory activity of dermal papilla cell. J Dermatol. 2014;41:84–91.

    Article  CAS  PubMed  Google Scholar 

  25. Tsai SY, Sennett R, Rezza A, et al. Wnt/beta-catenin signaling in dermal condensates is required for hair follicle formation. Dev Biol. 2014;385:179–88.

    Article  CAS  PubMed  Google Scholar 

  26. Leiros GJ, Attorresi AI, Balana ME. Hair follicle stem cell differentiation is inhibited through cross-talk between Wnt/beta-catenin and androgen signalling in dermal papilla cells from patients with androgenetic alopecia. Br J Dermatol. 2012;166:1035–42.

    Article  CAS  PubMed  Google Scholar 

  27. Premanand A, Rajkumari BR. In silico analysis of gene expression data from bald frontal and haired occipital scalp to identify candidate genes in male androgenetic alopecia. Arch Dermatol Res. 2019;311:815–24.

    Article  CAS  PubMed  Google Scholar 

  28. Pierard-Franchimont C, Pierard GE. Alterations in hair follicle dynamics in women. Biomed Res Int 2013;2013:957432.

  29. Mirmirani P. Managing hair loss in midlife women. Maturitas. 2013;74:119–22.

    Article  PubMed  Google Scholar 

  30. Mirmirani P. Hormonal changes in menopause: do they contribute to a “midlife hair crisis” in women? Br J Dermatol. 2011;165(Suppl 3):7–11.

    Article  CAS  PubMed  Google Scholar 

  31. Rossini M, Gatti D, Adami S. Involvement of WNT/beta-catenin signaling in the treatment of osteoporosis. Calcif Tissue Int. 2013;93:121–32.

    Article  CAS  PubMed  Google Scholar 

  32. Hanley DA, Adachi JD, Bell A, Brown V. Denosumab: mechanism of action and clinical outcomes. Int J Clin Pract. 2012;66:1139–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Beer L MM, Ankersmit HJ. Cell secretome based drug substances in regenerative medicine: when regulatory affairs meet basic science. Annals of Translational Medicine 2017;5.

  34. Vizoso FJEN, Cid S, Schneider J, Perez-Fernandez R. Mesenchymal stem cell secretome: toward cell-free therapeutic strategies in regenerative medicine. Int J Mol Sci. 2017;18:1852.

    Article  PubMed Central  Google Scholar 

  35. Zanzottera F LE, Trovato L, Icardi A, Graziano A. Adipose derived stem cells and growth factors applied on hair transplantation. Follow-up of clinical outcome. Journal of Cosmetics, Dermatological Sciences and Applications 2014;4:268–274.

  36. Elmaadawi IH, Mohamed BM, Ibrahim ZAS, et al. Stem cell therapy as a novel therapeutic intervention for resistant cases of alopecia areata and androgenetic alopecia. J Dermatolog Treat. 2018;29:431–40.

    Article  PubMed  Google Scholar 

  37. Gentile P, Cole JP, Cole MAet al. Evaluation of not-activated and activated PRP in hair loss treatment: role of growth factor and cytokine concentrations obtained by different collection systems. Int J Mol Sci 2017;18.

  38. Yoo BY, Shin YH, Yoon HH, Seo YK, Song KY, Park JK. Application of mesenchymal stem cells derived from bone marrow and umbilical cord in human hair multiplication. J Dermatol Sci. 2010;60:74–83.

    Article  CAS  PubMed  Google Scholar 

  39. Gentile P, Garcovich S. Advances in regenerative stem cell therapy in androgenic alopecia and hair loss: wnt pathway, growth-factor, and mesenchymal stem cell signaling impact analysis on cell growth and hair follicle development. Cells 2019;8.

  40. Won CH, Yoo HG, Kwon OS, et al. Hair growth promoting effects of adipose tissue-derived stem cells. J Dermatol Sci. 2010;57:134–7.

    Article  CAS  PubMed  Google Scholar 

  41. Park BS, Kim WS, Choi JS, et al. Hair growth stimulated by conditioned medium of adipose-derived stem cells is enhanced by hypoxia: evidence of increased growth factor secretion. Biomed Res. 2010;31:27–34.

    Article  CAS  PubMed  Google Scholar 

  42. Choi H CE, Yoon S, et al. Effect of exosomes from human adipose-derived stem cells on hair growth. J Extracell Vesicles 2019;8:PF08.02.

  43. Shin H, Ryu HH, Kwon O, Park BS, Jo SJ. Clinical use of conditioned media of adipose tissue-derived stem cells in female pattern hair loss: a retrospective case series study. Int J Dermatol. 2015;54:730–5.

    Article  PubMed  Google Scholar 

  44. Kim HO CS-M, Kim H-S. Mesenchymal stem cell-derived secretome and microvesicles as a cell-free therapeutics for neurodegenerative disorders. Tissue Engineering and Regenerative Medicine 2013;10:93–101.

  45. Egger A, Tomic-Canic M, Tosti A. Advances in stem cell-based therapy for hair loss. CellR4 Repair Replace Regen Reprogram 2020;8.

  46. Fukuoka H, Narita K, Suga H. Hair regeneration therapy: application of adipose-derived stem cells. Curr Stem Cell Res Ther. 2017;12:531–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fukuoka H, Suga H. Hair regeneration treatment using adipose-derived stem cell conditioned medium: follow-up with trichograms. Eplasty 2015;15:e10.

  48. Fukuoka HSH, Narita K, Watanabe R, Shintani S. The latest advance in hair regeneration therapy using proteins secreted by adipose-derived stem cells. Am J Cosmet Surg. 2012;29:273–82.

    Article  Google Scholar 

  49. Narita K, Fukuoka H, Sekiyama T, Suga H, Harii K. Sequential scalp assessment in hair regeneration therapy using an adipose-derived stem cell-conditioned medium. Dermatol Surg. 2020;46:819–25.

    Article  CAS  PubMed  Google Scholar 

  50. Won CH, Park GH, Wu X, et al. The basic mechanism of hair growth stimulation by adipose-derived stem cells and their secretory factors. Curr Stem Cell Res Ther. 2017;12:535–43.

    Article  CAS  PubMed  Google Scholar 

  51. Anderi R, Makdissy N, Azar A, Rizk F, Hamade A. Cellular therapy with human autologous adipose-derived adult cells of stromal vascular fraction for alopecia areata. Stem Cell Res Ther. 2018;9:141.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Perez-Meza D, Ziering C, Sforza M, Krishnan G, Ball E, Daniels E. Hair follicle growth by stromal vascular fraction-enhanced adipose transplantation in baldness. Stem Cells Cloning. 2017;10:1–10.

    PubMed  PubMed Central  Google Scholar 

  53. Bu ZY, Wu LM, Yu XH, Zhong JB, Yang P, Chen J. Isolation and characterization of in vitro culture of hair follicle cells differentiated from umbilical cord blood mesenchymal stem cells. Exp Ther Med. 2017;14:303–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bak DH, Lee E, Choi MJ, et al. Protective effects of human umbilical cord bloodderived mesenchymal stem cells against dexamethasoneinduced apoptotic cell death in hair follicles. Int J Mol Med. 2020;45:556–68.

    CAS  PubMed  Google Scholar 

  55. Teixeira FG, Carvalho MM, Panchalingam KM, et al. Impact of the secretome of human mesenchymal stem cells on brain structure and animal behavior in a rat model of Parkinson’s disease. Stem Cells Transl Med. 2017;6:634–46.

    Article  CAS  PubMed  Google Scholar 

  56. Khosravi A, Cutler CM, Kelly MH, et al. Determination of the elimination half-life of fibroblast growth factor-23. J Clin Endocrinol Metab. 2007;92:2374–7.

    Article  CAS  PubMed  Google Scholar 

  57. Chevillet JR, Kang Q, Ruf IK, et al. Quantitative and stoichiometric analysis of the microRNA content of exosomes. Proc Natl Acad Sci U S A. 2014;111:14888–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Liu Y, Wang H, Wang J. Exosomes as a novel pathway for regulating development and diseases of the skin. Biomed Rep. 2018;8:207–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Maguire G. Stem cell therapy without the cells. Commun Integr Biol 2013;6:e26631.

  60. Liu R, Liu J, Ji X, Liu Y. Synthetic nucleic acids delivered by exosomes: a potential therapeutic for generelated metabolic brain diseases. Metab Brain Dis. 2013;28:551–62.

    Article  CAS  PubMed  Google Scholar 

  61. Gross JC, Chaudhary V, Bartscherer K, Boutros M. Active Wnt proteins are secreted on exosomes. Nat Cell Biol. 2012;14:1036–45.

    Article  CAS  PubMed  Google Scholar 

  62. Carrasco E, Calvo MI, Blazquez-Castro A, et al. Photoactivation of ROS production in situ transiently activates cell proliferation in mouse skin and in the hair follicle stem cell niche promoting hair growth and wound healing. J Invest Dermatol. 2015;135:2611–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Myung P, Ito M. Dissecting the bulge in hair regeneration. J Clin Invest. 2012;122:448–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Taghiabadi E, Nilforoushzadeh MA, Aghdami N. Maintaining hair inductivity in human dermal papilla cells: a review of effective methods. Skin Pharmacol Physiol. 2020;33:280–92.

    Article  CAS  PubMed  Google Scholar 

  65. Yan H, Gao Y, Ding Q, et al. Exosomal micro RNAs derived from dermal papilla cells mediate hair follicle stem cell proliferation and differentiation. Int J Biol Sci. 2019;15:1368–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Rajendran RL, Gangadaran P, Bak SS, et al. Extracellular vesicles derived from MSCs activates dermal papilla cell in vitro and promotes hair follicle conversion from telogen to anagen in mice. Sci Rep. 2017;7:15560.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Zhou M, Hu M, He S, et al. Effects of RSC96 Schwann cell-derived exosomes on proliferation, senescence, and apoptosis of dorsal root ganglion cells in vitro. Med Sci Monit. 2018;24:7841–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. le Riche A, Aberdam E, Marchand L, et al. Extracellular vesicles from activated dermal fibroblasts stimulate hair follicle growth through dermal papilla-secreted norrin. Stem Cells. 2019;37:1166–75.

    Article  PubMed  Google Scholar 

  69. Chen Y, Huang J, Chen R, et al. Sustained release of dermal papilla-derived extracellular vesicles from injectable microgel promotes hair growth. Theranostics. 2020;10:1454–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kwack MH, Seo CH, Gangadaran P, et al. Exosomes derived from human dermal papilla cells promote hair growth in cultured human hair follicles and augment the hair-inductive capacity of cultured dermal papilla spheres. Exp Dermatol. 2019;28:854–7.

    Article  CAS  PubMed  Google Scholar 

  71. Huh C-H KS. Exosome for hair regnereation: from bench to bedside. J Am Acad Dermatol 2019.

  72. Lai CP, Mardini O, Ericsson M, et al. Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano. 2014;8:483–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Stenqvist AC, Nagaeva O, Baranov V, Mincheva-Nilsson L. Exosomes secreted by human placenta carry functional Fas ligand and TRAIL molecules and convey apoptosis in activated immune cells, suggesting exosome-mediated immune privilege of the fetus. J Immunol. 2013;191:5515–23.

    Article  CAS  PubMed  Google Scholar 

  74. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.

    Article  CAS  Google Scholar 

  75. Dong L, Hao H, Liu J, et al. A conditioned medium of umbilical cord mesenchymal stem cells overexpressing Wnt7a promotes wound repair and regeneration of hair follicles in mice. Stem Cells Int. 2017;2017:3738071.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Dong L, Hao H, Liu J, et al. Wnt1a maintains characteristics of dermal papilla cells that induce mouse hair regeneration in a 3D preculture system. J Tissue Eng Regen Med. 2017;11:1479–89.

    Article  CAS  PubMed  Google Scholar 

  77. Choi N, Choi J, Kim JH, et al. Generation of trichogenic adipose-derived stem cells by expression of three factors. J Dermatol Sci. 2018;92:18–29.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Facial Plastic & Reconstructive Surgery, Department of Otolaryngology—Head & Neck Surgery, University of Kansas, Medical Center, Kansas City, KS, USA

    Natalie A. Krane

  2. CEO, Endocrinology Associates, Columbus, OH, USA

    Elena A. Christofides

  3. Albert Einstein College of Medicine, 120 East 56th Street, Suite 800, Bronx, New York, NY, 10022, USA

    Yael Halaas

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  1. Natalie A. Krane
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Correspondence to Yael Halaas.

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Krane, N.A., Christofides, E.A. & Halaas, Y. Advances in Hair Restoration. Curr Otorhinolaryngol Rep 9, 436–441 (2021). https://doi.org/10.1007/s40136-021-00368-0

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