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Exploring the Potential of Mesenchymal Stem Cell–Derived Exosomes for the Treatment of Alopecia

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Abstract

As per the latest survey statistic reports by the International Society of Hair Restoration Surgery (ISHRS), alopecia increasingly affects more men and women of all ages over the decade owing to a decreased regenerative capability of the hair follicles and other factors that affect the hair cycle. Current therapeutic strategies are limited, and their outcomes are not satisfactory. This calls for an increased worldwide demand for effective hair restoration therapies. Here, we review the highly promising potential of stem cell–derived exosomes with emphasis on current efforts and limitations in its clinical translation for the treatment of alopecia. Recent advancements in exosome therapy are posed on their potential translation into clinical setting by urging adoption of regulatory compliance and quality control practices.

Lay Summary

Hair loss increasingly affects more men and women of all ages. It is pernicious to an individual both physically and psychologically. Currently available treatments are limited, and their outcomes are not satisfactory. This calls for an increased worldwide demand for an effective hair restoration treatment. Here, we discuss recent research using stem cells that are known to provide the signals responsible for hair regrowth.

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References

  1. Mohammadi P, Youssef KK, Abbasalizadeh S, Baharvand H, Aghdami N. Human hair reconstruction: close, but yet so far. Stem Cells Dev. 2016;25(23):1767–79.

    Article  Google Scholar 

  2. Owczarczyk-Saczonek A, Krajewska-Włodarczyk M, Kruszewska A, Banasiak Ł, Placek W, Maksymowicz W, et al. Therapeutic potential of stem cells in follicle regeneration. Stem Cells Int. 2018;2018:e1049641.

    Article  Google Scholar 

  3. Kanti V, Messenger A, Dobos G, Reygagne P, Finner A, Blumeyer A, et al. Evidence-based (S3) guideline for the treatment of androgenetic alopecia in women and in men – short version. J Eur Acad Dermatol Venereol. 2018;32(1):11–22.

    Article  CAS  Google Scholar 

  4. Ramos PM, Miot HA, Ramos PM, Miot HA. Female pattern hair loss: a clinical and pathophysiological review. An Bras Dermatol. 2015;90(4):529–43.

    Article  Google Scholar 

  5. Yuan A-R, Bian Q, Gao J-Q. Current advances in stem cell-based therapies for hair regeneration. Eur J Pharmacol. 2020;881:173197.

    Article  CAS  Google Scholar 

  6. Balañá ME, Charreau HE, Leirós GJ. Epidermal stem cells and skin tissue engineering in hair follicle regeneration. World J Stem Cells. 2015;7(4):711–27.

    Article  Google Scholar 

  7. Gentile P, Cole JP, Cole MA, Garcovich S, Bielli A, Scioli MG, et 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. https://doi.org/10.3390/ijms18020408.

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

  9. Beer L, Mildner M, Ankersmit HJ. Cell secretome based drug substances in regenerative medicine: when regulatory affairs meet basic science. Ann Transl Med. 2017. https://doi.org/10.21037/atm.2017.03.50.

  10. Han C, Sun X, Liu L, Jiang H, Shen Y, Xu X, et al. Exosomes and their therapeutic potentials of stem cells. Stem Cells Int. 2016;2016:1–11. https://doi.org/10.1155/2016/7653489.

    Article  CAS  Google Scholar 

  11. Cicero AL, Delevoye C, Gilles-Marsens F, Loew D, Dingli F, Guéré C, et al. Exosomes released by keratinocytes modulate melanocyte pigmentation. Nat Commun. 2015;6:7506. https://doi.org/10.1038/ncomms8506.

    Article  CAS  Google Scholar 

  12. Rajendran RL, Gangadaran P, Bak SS, Oh JM, Kalimuthu S, Lee HW, 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. https://doi.org/10.1038/s41598-017-15505-3.

    Article  CAS  Google Scholar 

  13. Saxena N, Mok K-W, Rendl M. An updated classification of hair follicle morphogenesis. Exp Dermatol. 2019;28(4):332–44.

    Article  Google Scholar 

  14. Jahoda C a B, Horne KA, Oliver RF. Induction of hair growth by implantation of cultured dermal papilla cells. Nature. 1984;311(5986):560–2.

    Article  CAS  Google Scholar 

  15. Sperling LC. Hair anatomy for the clinician. J Am Acad Dermatol. 1991;25(1, Part 1):1–17.

    Article  CAS  Google Scholar 

  16. Alonso L, Fuchs E. The hair cycle. J Cell Sci. 2006;119(3):391–3.

    Article  CAS  Google Scholar 

  17. Zhang P, Kling RE, Ravuri SK, Kokai LE, Rubin JP, Chai J, et al. A review of adipocyte lineage cells and dermal papilla cells in hair follicle regeneration. J Tissue Eng. 2014;5:2041731414556850.

    Article  Google Scholar 

  18. Tsai S-Y, Sennett R, Rezza A, Clavel C, Grisanti L, Zemla R, et al. Wnt/β-catenin signaling in dermal condensates is required for hair follicle formation. Dev Biol. 2014;385(2):179–88.

    Article  CAS  Google Scholar 

  19. Millar SE. Molecular mechanisms regulating hair follicle development. J Invest Dermatol. 2002;118(2):216–25.

    Article  CAS  Google Scholar 

  20. St-Jacques B, Dassule HR, Karavanova I, Botchkarev VA, Li J, Danielian PS, et al. Sonic hedgehog signaling is essential for hair development. Curr Biol CB. 1998;8(19):1058–68.

    Article  CAS  Google Scholar 

  21. Martel JL, Miao JH, Badri T (2020) Anatomy, Hair follicle. StatPearls.

  22. Kunz M, Seifert B, Trüeb RM. Seasonality of hair shedding in healthy women complaining of hair loss. Dermatology. 2009;219(2):105–10.

    Article  Google Scholar 

  23. Hsiang EY, Semenov YR, Aguh C, Kwatra SG. Seasonality of hair loss: a time series analysis of Google Trends data 2004-2016. Br J Dermatol. 2018;178(4):978–9.

    Article  CAS  Google Scholar 

  24. Neste DV. Thickness, medullation and growth rate of female scalp hair are subject to significant variation according to pigmentation and scalp location during ageing. Eur J Dermatol. 2004;14(1):28–32.

    Google Scholar 

  25. Sakai Y, Kishimoto J, Demay MB. Metabolic and cellular analysis of alopecia in vitamin D receptor knockout mice. J Clin Invest. 2001;107(8):961–6.

    Article  CAS  Google Scholar 

  26. Mejia LA, Hodges RE, Rucker RB. Clinical signs of anemia in vitamin A-deficient rats. Am J Clin Nutr. 1979;32(7):1439–44.

    Article  CAS  Google Scholar 

  27. Swenerton H, Hurley LS. Zinc deficiency in rhesus and bonnet monkeys, including effects on reproduction. J Nutr. 1980;110(3):575–83.

    Article  CAS  Google Scholar 

  28. Kwack MH, Ahn JS, Kim MK, Kim JC, Sung YK. Dihydrotestosterone-inducible IL-6 inhibits elongation of human hair shafts by suppressing matrix cell proliferation and promotes regression of hair follicles in mice. J Invest Dermatol. 2012;132(1):43–9.

    Article  CAS  Google Scholar 

  29. Dl P. Hypothyroidism in dogs: 66 cases (1987-1992). J Am Vet Med Assoc. 1994;204(5):761–7.

    Google Scholar 

  30. Toribio J, Quiñones PA. Hereditary hypotrichosis simplex of the scalp. Br J Dermatol. 1974;91(6):687–96.

    Article  CAS  Google Scholar 

  31. Annessi G, Lombardo G, Gobello T, Puddu P. A clinicopathologic study of scarring alopecia due to lichen planus: comparison with scarring alopecia in discoid lupus erythematosus and pseudopelade. Am J Dermatopathol. 1999;21(4):324–31.

    Article  CAS  Google Scholar 

  32. Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem. 1987;262(19):9412–20.

    Article  CAS  Google Scholar 

  33. Kabe Y, Suematsu M, Sakamoto S, Hirai M, Koike I, Hishiki T, et al. Development of a highly sensitive device for counting the number of disease-specific exosomes in human sera. Clin Chem. 2018;64(10):1463–73.

    Article  CAS  Google Scholar 

  34. Malkud S. Telogen effluvium: a review. J Clin Diagn Res JCDR. 2015;9(9):WE01–3.

    Google Scholar 

  35. Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. 2008;3(3):301–13.

    Article  CAS  Google Scholar 

  36. Chang C-L, Sung P-H, Chen K-H, Shao PL, Yang CC, Cheng BC, et al. Adipose-derived mesenchymal stem cell-derived exosomes alleviate overwhelming systemic inflammatory reaction and organ damage and improve outcome in rat sepsis syndrome. Am J Transl Res. 2018;10(4):1053–70.

    CAS  Google Scholar 

  37. Bianco P, Robey PG, Simmons PJ. Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell. 2008;2(4):313–9.

    Article  CAS  Google Scholar 

  38. Karp JM, Leng Teo GS. Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell. 2009;4(3):206–16.

    Article  CAS  Google Scholar 

  39. Spees JL, Lee RH, Gregory CA. Mechanisms of mesenchymal stem/stromal cell function. Stem Cell Res Ther. 2016;7(1):125.

    Article  Google Scholar 

  40. Akyurekli C, Le Y, Richardson RB, Fergusson D, Tay J, Allan DS. A systematic review of preclinical studies on the therapeutic potential of mesenchymal stromal cell-derived microvesicles. Stem Cell Rev Rep. 2015;11(1):150–60.

    Article  CAS  Google Scholar 

  41. Tkach M, Théry C. Communication by extracellular vesicles: where we are and where we need to go. Cell. 2016;164(6):1226–32.

    Article  CAS  Google Scholar 

  42. Pratt CH, King LE, Messenger AG, Christiano AM, Sundberg JP. Alopecia areata. Nat Rev Dis Primer. 2017;3(1):1–17.

    Google Scholar 

  43. Huang X, Yuan T, Tschannen M, Sun Z, Jacob H, du M, et al. Characterization of human plasma-derived exosomal RNAs by deep sequencing. BMC Genomics. 2013;14:319.

    Article  CAS  Google Scholar 

  44. Kupcova Skalnikova H. Proteomic techniques for characterisation of mesenchymal stem cell secretome. Biochimie. 2013;95(12):2196–211.

    Article  CAS  Google Scholar 

  45. Dey-Rao R, Sinha AA. A genomic approach to susceptibility and pathogenesis leads to identifying potential novel therapeutic targets in androgenetic alopecia. Genomics. 2017;109(3–4):165–76.

    Article  CAS  Google Scholar 

  46. Lu K, Li H-Y, Yang K, Wu J-L, Cai X-W, Zhou Y, et al. Exosomes as potential alternatives to stem cell therapy for intervertebral disc degeneration: in-vitro study on exosomes in interaction of nucleus pulposus cells and bone marrow mesenchymal stem cells. Stem Cell Res Ther. 2017;8(1):108.

    Article  Google Scholar 

  47. Colao IL, Corteling R, Bracewell D, Wall I. Manufacturing exosomes: a promising therapeutic platform. Trends Mol Med. 2018;24(3):242–56.

    Article  CAS  Google Scholar 

  48. Gimona M, Pachler K, Laner-Plamberger S, Schallmoser K, Rohde E. Manufacturing of human extracellular vesicle-based therapeutics for clinical use. Int J Mol Sci. 2017;18(6):1190.

    Article  Google Scholar 

  49. Whitford W, Guterstam P. Exosome manufacturing status. Future Med Chem. 2019;11(10):1225–36.

    Article  CAS  Google Scholar 

  50. Mendt M, Kamerkar S, Sugimoto H, et al. Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight. 2018. https://doi.org/10.1172/jci.insight.99263.

  51. Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018;7. https://doi.org/10.1080/20013078.2018.1535750.

  52. Witwer KW, Soekmadji C, Hill AF, Wauben MH, Buzás EI, di Vizio D, et al. Updating the MISEV minimal requirements for extracellular vesicle studies: building bridges to reproducibility. J Extracell Vesicles. 2017;6. https://doi.org/10.1080/20013078.2017.1396823.

  53. Yi YW, Lee JH, Kim S-Y, Pack C-G, Ha DH, Park SR, et al. Advances in analysis of biodistribution of exosomes by molecular imaging. Int J Mol Sci. 2020;21. https://doi.org/10.3390/ijms21020665.

  54. Andriolo G, Provasi E, Lo Cicero V, Brambilla A, Soncin S, Torre T, et al. Exosomes from human cardiac progenitor cells for therapeutic applications: development of a GMP-grade manufacturing method. Front Physiol. 2018;9. https://doi.org/10.3389/fphys.2018.01169.

  55. an der Pol E, Coumans F a W, Grootemaat AE, Gardiner C, Sargent IL, Harrison P, et al. Particle size distribution of exosomes and microvesicles determined by transmission electron microscopy, flow cytometry, nanoparticle tracking analysis, and resistive pulse sensing. J Thromb Haemost JTH. 2014;12(7):1182–92.

    Article  Google Scholar 

  56. Carnell-Morris P, Tannetta D, Siupa A, Hole P, Dragovic R. Analysis of extracellular vesicles using fluorescence nanoparticle tracking analysis. Methods Mol Biol Clifton NJ. 2017;1660:153–73.

    Article  CAS  Google Scholar 

  57. Ma L, Zhu S, Tian Y, Zhang W, Wang S, Chen C, et al. Label-free analysis of single viruses with a resolution comparable to that of electron microscopy and the throughput of flow cytometry. Angew Chem Int Ed Engl. 2016;55(35):10239–43.

    Article  CAS  Google Scholar 

  58. Takeuchi R, Katagiri W, Endo S, Kobayashi T. Exosomes from conditioned media of bone marrow-derived mesenchymal stem cells promote bone regeneration by enhancing angiogenesis. PloS One. 2019;14(11):e0225472.

    Article  CAS  Google Scholar 

  59. Danielson KM, Estanislau J, Tigges J, Toxavidis V, Camacho V, Felton EJ, et al. Diurnal variations of circulating extracellular vesicles measured by nano flow cytometry. PloS One. 2016;11(1):e0144678.

    Article  Google Scholar 

  60. Nizamudeen Z, Markus R, Lodge R, Parmenter C, Platt M, Chakrabarti L, et al. Rapid and accurate analysis of stem cell-derived extracellular vesicles with super resolution microscopy and live imaging. Biochim Biophys Acta Mol Cell Res. 2018;1865(12):1891–900.

    Article  CAS  Google Scholar 

  61. Görgens A, Bremer M, Ferrer-Tur R, Murke F, Tertel T, Horn PA, et al. Optimisation of imaging flow cytometry for the analysis of single extracellular vesicles by using fluorescence-tagged vesicles as biological reference material. J Extracell Vesicles. 2019;8(1):1587567.

    Article  Google Scholar 

  62. Coumans FAW, Brisson AR, Buzas EI, Dignat-George F, Drees EEE, el-Andaloussi S, et al. Methodological guidelines to study extracellular vesicles. Circ Res. 2017;120(10):1632–48.

    Article  CAS  Google Scholar 

  63. Rajendran RL, Gangadaran P, Bak SS, Oh JM, Kalimuthu S, Lee HW, 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(1):15560.

    Article  Google Scholar 

  64. Pennisi D, Bowles J, Nagy A, Muscat G, Koopman P. Mice null for sox18 are viable and display a mild coat defect. Mol Cell Biol. 2000;20(24):9331–6.

    Article  CAS  Google Scholar 

  65. Carrasco E, Soto-Heredero G, Mittelbrunn M. The role of extracellular vesicles in cutaneous remodeling and hair follicle dynamics. Int J Mol Sci. 2019;20(11):2Bmp758.

    Article  Google Scholar 

  66. Zhou L, Wang H, Jing J, Yu L, Wu X, Lu Z. Regulation of hair follicle development by exosomes derived from dermal papilla cells. Biochem Biophys Res Commun. 2018;500(2):325–32.

    Article  CAS  Google Scholar 

  67. Kwack MH, Seo CH, Gangadaran P, Ahn B-C, Kim MK, Kim JC, 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(7):854–7.

    Article  CAS  Google Scholar 

  68. le Riche A, Aberdam E, Marchand L, Frank E, Jahoda C, Petit I, et al. Extracellular vesicles from activated dermal fibroblasts stimulate hair follicle growth through dermal papilla-secreted norrin. Stem Cells. 2019;37(9):1166–75.

    Article  Google Scholar 

  69. Yang G, Chen Q, Wen D, Chen Z, Wang J, Chen G, et al. A therapeutic microneedle patch made from hair-derived keratin for promoting hair regrowth. ACS Nano. 2019;13(4):4354–60.

    Article  CAS  Google Scholar 

  70. Ak G, Hj R, Halaas Y, Rapaport JA. Exosomes: a new effective non-surgical therapy for androgenetic alopecia? Skinmed. 2020;18(2):96–100.

    Google Scholar 

  71. Huh CH, Kwon S. Exosome for hair regeneration: from bench to bedside. J Am Acad Dermatol. 2019;81(4):AB62. https://doi.org/10.1016/j.jaad.2019.06.256.

    Article  Google Scholar 

  72. Maguire G. The safe and efficacious use of secretome from fibroblasts and adipose-derived (but not bone marrow-derived) mesenchymal stem cells for skin therapeutics. J Clin Aesthetic Dermatol. 2019;12(8):E57–69.

    Google Scholar 

  73. Chen TS, Arslan F, Yin Y, Tan SS, Lai RC, Choo ABH, et al. Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs. J Transl Med. 2011;9:47.

    Article  CAS  Google Scholar 

  74. Lai RC, Yeo RWY, Padmanabhan J, Choo A, de Kleijn DPV, Lim SK. Isolation and characterization of exosome from human embryonic stem cell-derived C-Myc-immortalized mesenchymal stem cells. Methods Mol Biol Clifton NJ. 2016;1416:477–94.

    Article  CAS  Google Scholar 

  75. Kerure AS, Patwardhan N. Complications in hair transplantation. J Cutan Aesthetic Surg. 2018;11(4):182–9.

    Article  Google Scholar 

  76. Plikus M, Wang WP, Liu J, Wang X, Jiang TX, Chuong CM. Morpho-regulation of ectodermal organs: integument pathology and phenotypic variations in K14-Noggin engineered mice through modulation of bone morphogenic protein pathway. Am J Pathol. 2004;164(3):1099–114.

    Article  CAS  Google Scholar 

  77. Pennisi D, Gardner J, Chambers D, Hosking B, Peters J, Muscat G, et al. Mutations in Sox18 underlie cardiovascular and hair follicle defects in ragged mice. Nat Genet. 2000;24(4):434–7.

    Article  CAS  Google Scholar 

  78. Cui CY, Kunisada M, Piao Y, Childress V, Ko MS, Schlessinger D. Dkk4 and Eda regulate distinctive developmental mechanisms for subtypes of mouse hair. PloS one. 2010;5(4):e10009.

    Article  Google Scholar 

  79. Cetera M, Leybova L, Joyce B, Devenport D. Counter-rotational cell flows drive morphological and cell fate asymmetries in mammalian hair follicles. Nat Cell Biol. 2018;20(5):541–52.

    Article  CAS  Google Scholar 

  80. Foitzik K, Paus R, Doetschman T, Dotto GP. The TGF-β2 isoform is both a required and sufficient inducer of murine hair follicle morphogenesis. Dev Biol. 1999;212(2):278–89.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the Company of Biologists for permitting us to reproduce the published figure depicting the hair cycle from the cited article. We also thank Ar. Jobin Joseph Abraham for the technical help in preparation of scientific image illustrations for the manuscript.

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All Supporting data is made available within the manuscript.

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Authors and Affiliations

  1. Kerala Academy of Sciences, Sasthra Bhavan, Pattom, Thiruvananthapuram, Kerala, 695004, India

    Amita Ajit

  2. Ernakulum, India

    M. Devika Nair

  3. Department of Health Research, 2nd Floor, IRCS Building, 1, Red Cross Road, New Delhi, 110001, India

    Balu Venugopal

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  1. Amita Ajit
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Contributions

Dr. Amita Ajit: Conceptualization; methodology; investigation; resources; supervision; project administration; validation; visualization; original drafting; review and editing.

M Devika Nair: Literature search; resources; data acquisition, manuscript preparation, original drafting.

Balu Venugopal: Manuscript review, manuscript preparation, literature search.

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Correspondence to Amita Ajit.

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Ajit, A., Nair, M.D. & Venugopal, B. Exploring the Potential of Mesenchymal Stem Cell–Derived Exosomes for the Treatment of Alopecia. Regen. Eng. Transl. Med. 7, 119–128 (2021). https://doi.org/10.1007/s40883-021-00204-3

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