The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지
DOI QR코드

DOI QR Code

Human umbilical cord blood mesenchymal stem cells engineered to overexpress growth factors accelerate outcomes in hair growth

  • Bak, Dong Ho (Department of Dermatology, College of Medicine, Chung-Ang University) ;
  • Choi, Mi Ji (Department of Dermatology, College of Medicine, Chung-Ang University) ;
  • Kim, Soon Re (Department of Dermatology, College of Medicine, Chung-Ang University) ;
  • Lee, Byung Chul (Department of Dermatology, College of Medicine, Chung-Ang University) ;
  • Kim, Jae Min (Department of Medicine, Graduate School, Chung-Ang University) ;
  • Jeon, Eun Su (Biomedical Research Institute, R&D Center, MEDIPOST Co., Ltd.) ;
  • Oh, Wonil (Biomedical Research Institute, R&D Center, MEDIPOST Co., Ltd.) ;
  • Lim, Ee Seok (Thema Dermatologic Clinic) ;
  • Park, Byung Cheol (Department of Dermatology, Dankook Medical College) ;
  • Kim, Moo Joong (Fort Hays State University) ;
  • Na, Jungtae (Department of Dermatology, College of Medicine, Chung-Ang University) ;
  • Kim, Beom Joon (Department of Dermatology, College of Medicine, Chung-Ang University)
  • Received : 2018.04.03
  • Accepted : 2018.07.19
  • Published : 2018.09.01
Download PDF
⟨ Previous Next ⟩

Abstract

Human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) are used in tissue repair and regeneration; however, the mechanisms involved are not well understood. We investigated the hair growth-promoting effects of hUCB-MSCs treatment to determine whether hUCB-MSCs enhance the promotion of hair growth. Furthermore, we attempted to identify the factors responsible for hair growth. The effects of hUCB-MSCs on hair growth were investigated in vivo, and hUCB-MSCs advanced anagen onset and hair follicle neogeneration. We found that hUCB-MSCs co-culture increased the viability and up-regulated hair induction-related proteins of human dermal papilla cells (hDPCs) in vitro. A growth factor antibody array revealed that secretory factors from hUCB-MSCs are related to hair growth. Insulin-like growth factor binding protein-1 (IGFBP-1) and vascular endothelial growth factor (VEGF) were increased in co-culture medium. Finally, we found that IGFBP-1, through the co-localization of an IGF-1 and IGFBP-1, had positive effects on cell viability; VEGF secretion; expression of alkaline phosphatase (ALP), CD133, and ${\beta}-catenin$; and formation of hDPCs 3D spheroids. Taken together, these data suggest that hUCB-MSCs promote hair growth via a paracrine mechanism.

Keywords

References

  1. Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab. 1961;21:1440-1447. https://doi.org/10.1210/jcem-21-11-1440
  2. Harada T, Izaki S, Tsutsumi H, Kobayashi M, Kitamura K. Apoptosis of hair follicle cells in the second-degree burn wound unders hypernatremic conditions. Burns. 1998;24:464-469. https://doi.org/10.1016/S0305-4179(98)00034-5
  3. Leyden J, Dunlap F, Miller B, Winters P, Lebwohl M, Hecker D, Kraus S, Baldwin H, Shalita A, Draelos Z, Markou M, Thiboutot D, Rapaport M, Kang S, Kelly T, Pariser D, Webster G, Hordinsky M, Rietschel R, Katz HI, Terranella L, Best S, Round E, Waldstreicher J. Finasteride in the treatment of men with frontal male pattern hair loss. J Am Acad Dermatol. 1999;40:930-937. https://doi.org/10.1016/S0190-9622(99)70081-2
  4. Sinclair R. Male pattern androgenetic alopecia. BMJ. 1998;317:865-869. https://doi.org/10.1136/bmj.317.7162.865
  5. Kligman AM. Pathologic dynamics of human hair loss. I. Telogen effuvium. Arch Dermatol. 1961;83:175-198. https://doi.org/10.1001/archderm.1961.01580080005001
  6. Rogers NE, Avram MR. Medical treatments for male and female pattern hair loss. J Am Acad Dermatol. 2008;59:547-566. https://doi.org/10.1016/j.jaad.2008.07.001
  7. Leavitt M, Perez-Meza D, Rao NA, Barusco M, Kaufman KD, Ziering C. Effects of finasteride (1 mg) on hair transplant. Dermatol Surg. 2005;31:1268-1276. https://doi.org/10.1097/00042728-200510000-00002
  8. Rossi A, Cantisani C, Melis L, Iorio A, Scali E, Calvieri S. Minoxidil use in dermatology, side effects and recent patents. Recent Pat Inflamm Allergy Drug Discov. 2012;6:130-136. https://doi.org/10.2174/187221312800166859
  9. Irwig MS, Kolukula S. Persistent sexual side effects of finasteride for male pattern hair loss. J Sex Med. 2011;8:1747-1753. https://doi.org/10.1111/j.1743-6109.2011.02255.x
  10. Olsen EA, Hordinsky M, Whiting D, Stough D, Hobbs S, Ellis ML, Wilson T, Rittmaster RS. The importance of dual 5alpha-reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus finasteride. J Am Acad Dermatol. 2006;55:1014-1023. https://doi.org/10.1016/j.jaad.2006.05.007
  11. Patwardhan N, Mysore V. Hair transplantation: standard guidelines of care. Indian J Dermatol Venereol Leprol. 2008;74 Suppl:S46-53.
  12. Alonso L, Fuchs E. The hair cycle. J Cell Sci. 2006;119:391-393. https://doi.org/10.1242/jcs.02793
  13. Chueh SC, Lin SJ, Chen CC, Lei M, Wang LM, Widelitz R, Hughes MW, Jiang TX, Chuong CM. Therapeutic strategy for hair regeneration: hair cycle activation, niche environment modulation, woundinduced follicle neogenesis, and stem cell engineering. Expert Opin Biol Ther. 2013;13:377-391. https://doi.org/10.1517/14712598.2013.739601
  14. Harkey MR. Anatomy and physiology of hair. Forensic Sci Int. 1993;63:9-18. https://doi.org/10.1016/0379-0738(93)90255-9
  15. Elliott K, Stephenson TJ, Messenger AG. Differences in hair follicle dermal papilla volume are due to extracellular matrix volume and cell number: implications for the control of hair follicle size and androgen responses. J Invest Dermatol. 1999;113:873-877. https://doi.org/10.1046/j.1523-1747.1999.00797.x
  16. Kwack MH, Sung YK, Chung EJ, Im SU, Ahn JS, Kim MK, Kim JC. Dihydrotestosterone-inducible dickkopf 1 from balding dermal papilla cells causes apoptosis in follicular keratinocytes. J Invest Dermatol. 2008;128:262-269. https://doi.org/10.1038/sj.jid.5700999
  17. Dallob AL, Sadick NS, Unger W, Lipert S, Geissler LA, Gregoire SL, Nguyen HH, Moore EC, Tanaka WK. The effect of finasteride, a 5 alpha-reductase inhibitor, on scalp skin testosterone and dihydrotestosterone concentrations in patients with male pattern baldness. J Clin Endocrinol Metab. 1994;79:703-706.
  18. El-Badri NS, Hakki A, Saporta S, Liang X, Madhusodanan S, Willing AE, Sanberg CD, Sanberg PR. Cord blood mesenchymal stem cells: Potential use in neurological disorders. Stem Cells Dev. 2006;15:497-506. https://doi.org/10.1089/scd.2006.15.497
  19. Chung JY, Song M, Ha CW, Kim JA, Lee CH, Park YB. Comparison of articular cartilage repair with different hydrogel-human umbilical cord blood-derived mesenchymal stem cell composites in a rat model. Stem Cell Res Ther. 2014;5:39. https://doi.org/10.1186/scrt427
  20. Kim JY, Kim DH, Kim JH, Yang YS, Oh W, Lee EH, Chang JW. Umbilical cord blood mesenchymal stem cells protect amyloid-${\beta}$42 neurotoxicity via paracrine. World J Stem Cells. 2012;4:110-116. https://doi.org/10.4252/wjsc.v4.i11.110
  21. Ng F, Boucher S, Koh S, Sastry KS, Chase L, Lakshmipathy U, Choong C, Yang Z, Vemuri MC, Rao MS, Tanavde V. PDGF, TGFbeta, and FGF signaling is important for differentiation and growth of mesenchymal stem cells (MSCs): transcriptional profiling can identify markers and signaling pathways important in differentiation of MSCs into adipogenic, chondrogenic, and osteogenic lineages. Blood. 2008;112:295-307. https://doi.org/10.1182/blood-2007-07-103697
  22. Seo Y, Yang SR, Jee MK, Joo EK, Roh KH, Seo MS, Han TH, Lee SY, Ryu PD, Jung JW, Seo KW, Kang SK, Kang KS. Human umbilical cord blood-derived mesenchymal stem cells protect against neuronal cell death and ameliorate motor deficits in Niemann Pick type C1 mice. Cell Transplant. 2011;20:1033-1047. https://doi.org/10.3727/096368910X545086
  23. Li XY, Zheng ZH, Li XY, Guo J, Zhang Y, Li H, Wang YW, Ren J, Wu ZB. 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. 2013;19:4893-4899. https://doi.org/10.2174/13816128113199990326
  24. Lee MJ, Yoon TG, Kang M, Kim HJ, Kang KS. Effect of subcutaneous treatment with human umbilical cord blood-derived multipotent stem cells on peripheral neuropathic pain in rats. Korean J Physiol Pharmacol. 2017;21:153-160. https://doi.org/10.4196/kjpp.2017.21.2.153
  25. Park HW, Kim Y, Chang JW, Yang YS, Oh W, Lee JM, Park HR, Kim DG, Paek SH. Effect of single and double administration of human umbilical cord blood-derived mesenchymal stem cells following focal cerebral ischemia in rats. Exp Neurobiol. 2017;26:55-65. https://doi.org/10.5607/en.2017.26.1.55
  26. Yang SE, Ha CW, Jung M, Jin HJ, Lee M, Song H, Choi S, Oh W, Yang YS. Mesenchymal stem/progenitor cells developed in cultures from UC blood. Cytotherapy. 2004;6:476-486. https://doi.org/10.1080/14653240410005041
  27. Olsen EA. Hair disorders. In: Irvine AD, Hoeger PH, Yan AC, editors. Harper's textbook of pediatric dermatology. Volume 1, 2, 3rd ed. 2011. p.148.1-148.35.
  28. Mounsey AL, Reed SW. Diagnosing and treating hair loss. Am Fam Physician. 2009;80:356-362.
  29. Cotsarelis G, Millar SE. Towards a molecular understanding of hair loss and its treatment. Trends Mol Med. 2001;7:293-301.
  30. Semenova E, Koegel H, Hasse S, Klatte JE, Slonimsky E, Bilbao D, Paus R, Werner S, Rosenthal N. Overexpression of mIGF-1 in keratinocytes improves wound healing and accelerates hair follicle formation and cycling in mice. Am J Pathol. 2008;173:1295-1310. https://doi.org/10.2353/ajpath.2008.071177
  31. 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;166:1035-1042. https://doi.org/10.1111/j.1365-2133.2012.10856.x
  32. Cardona-Gomez P, Perez M, Avila J, Garcia-Segura LM, Wandosell F. Estradiol inhibits GSK3 and regulates interaction of estrogen receptors, GSK3, and beta-catenin in the hippocampus. Mol Cell Neurosci. 2004;25:363-373. https://doi.org/10.1016/j.mcn.2003.10.008
  33. Armstrong DD, Wong VL, Esser KA. Expression of beta-catenin is necessary for physiological growth of adult skeletal muscle. Am J Physiol Cell Physiol. 2006;291:C185-188. https://doi.org/10.1152/ajpcell.00644.2005
  34. Dong L, Hao H, Xia L, Liu J, Ti D, Tong C, Hou Q, Han Q, Zhao Y, Liu H, Fu X, Han W. Treatment of MSCs with Wnt1a-conditioned medium activates DP cells and promotes hair follicle regrowth. Sci Rep. 2014;4:5432.
  35. Zheng Y, Du X, Wang W, Boucher M, Parimoo S, Stenn K. Organogenesis from dissociated cells: generation of mature cycling hair follicles from skin-derived cells. J Invest Dermatol. 2005;124:867-876. https://doi.org/10.1111/j.0022-202X.2005.23716.x
  36. Kang BM, Kwack MH, Kim MK, Kim JC, Sung YK. Sphere formation increases the ability of cultured human dermal papilla cells to induce hair follicles from mouse epidermal cells in a reconstitution assay. J Invest Dermatol. 2012;132:237-239. https://doi.org/10.1038/jid.2011.250
  37. Kwon TR, Oh CT, Choi EJ, Park HM, Han HJ, Ji HJ, Kim BJ. Human placental extract exerts hair growth-promoting effects through the GSK-$3{\beta}$ signaling pathway in human dermal papilla cells. Int J Mol Med. 2015;36:1088-1096. https://doi.org/10.3892/ijmm.2015.2316
  38. Iida M, Ihara S, Matsuzaki T. Hair cycle-dependent changes of alkaline phosphatase activity in the mesenchyme and epithelium in mouse vibrissal follicles. Dev Growth Differ. 2007;49:185-195. https://doi.org/10.1111/j.1440-169X.2007.00907.x
  39. Lin TC, Yen JM, Gong KB, Hsu TT, Chen LR. IGF-1/IGFBP-1 increases blastocyst formation and total blastocyst cell number in mouse embryo culture and facilitates the establishment of a stemcell line. BMC Cell Biol. 2003;4:14. https://doi.org/10.1186/1471-2121-4-14
  40. Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 1995;16:3-34.
  41. Baxter RC. Insulin-like growth factor (IGF) binding proteins: the role of serum IGFBPs in regulating IGF availability. Acta Paediatr Scand Suppl. 1991;372:107-114.
  42. Shapiro J, Madani S. Alopecia areata: diagnosis and management. Int J Dermatol. 1999;38 Suppl 1:19-24. https://doi.org/10.1046/j.1365-4362.1999.00004.x
  43. Rushton DH, Norris MJ, Dover R, Busuttil N. Causes of hair loss and the developments in hair rejuvenation. Int J Cosmet Sci. 2002;24:17-23. https://doi.org/10.1046/j.0412-5463.2001.00110.x
  44. Iguchi M, Hara M, Manome H, Kobayasi H, Tagami H, Aiba S. Communication network in the follicular papilla and connective tissue sheath through gap junctions in human hair follicles. Exp Dermatol. 2003;12:283-288. https://doi.org/10.1034/j.1600-0625.2003.120308.x
  45. Hibino T, Nishiyama T. Role of TGF-beta2 in the human hair cycle. J Dermatol Sci. 2004;35:9-18. https://doi.org/10.1016/j.jdermsci.2003.12.003
  46. Messenger AG. The control of hair growth: an overview. J Invest Dermatol. 1993;101(1 Suppl):4S-9S. https://doi.org/10.1016/0022-202X(93)90494-3
  47. Phinney DG. Biochemical heterogeneity of mesenchymal stem cell populations: clues to their therapeutic efficacy. Cell Cycle. 2007;6:2884-2889. https://doi.org/10.4161/cc.6.23.5095
  48. Wagner W, Wein F, Seckinger A, Frankhauser M, Wirkner U, Krause U, Blake J, Schwager C, Eckstein V, Ansorge W, Ho AD. Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood. Exp Hematol. 2005;33:1402-1416. https://doi.org/10.1016/j.exphem.2005.07.003
  49. Anderson DG, Markova D, An HS, Chee A, Enomoto-Iwamoto M, Markov V, Saitta B, Shi P, Gupta C, Zhang Y. Human umbilical cord blood-derived mesenchymal stem cells in the cultured rabbit intervertebral disc: a novel cell source for disc repair. Am J Phys Med Rehabil. 2013;92:420-429. https://doi.org/10.1097/PHM.0b013e31825f148a
  50. Liu GP, Li YL, Sun J, Cui L, Zhang WJ, Cao YL. Repair of calvarial defects with human umbilical cord blood derived mesenchymal stem cells and demineralized bone matrix in athymic rats. Zhonghua Zheng Xing Wai Ke Za Zhi. 2010;26:34-38.
  51. Chen L, Tredget EE, Wu PY, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One. 2008;3:e1886. https://doi.org/10.1371/journal.pone.0001886
  52. Guo J, Lin GS, Bao CY, Hu ZM, Hu MY. Anti-inflammation role for mesenchymal stem cells transplantation in myocardial infarction. Inflammation. 2007;30:97-104. https://doi.org/10.1007/s10753-007-9025-3
  53. Xie Z, Hao H, Tong C, Cheng Y, Liu J, Pang Y, Si Y, Guo Y, Zang L, Mu Y, Han W. Human umbilical cord-derived mesenchymal stem cells elicit macrophages into an anti-inflammatory phenotype to alleviate insulin resistance in type 2 diabetic rats. Stem Cells. 2016;34:627-639. https://doi.org/10.1002/stem.2238
  54. Arthur A, Zannettino A, Gronthos S. The therapeutic applications of multipotential mesenchymal/stromal stem cells in skeletal tissue repair. J Cell Physiol. 2009;218:237-245. https://doi.org/10.1002/jcp.21592
  55. Davis ME, Hsieh PC, Takahashi T, Song Q, Zhang S, Kamm RD, Grodzinsky AJ, Anversa P, Lee RT. Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction. Proc Natl Acad Sci U S A. 2006;103:8155-8160. https://doi.org/10.1073/pnas.0602877103
  56. Sukhanov S, Higashi Y, Shai SY, Vaughn C, Mohler J, Li Y, Song YH, Titterington J, Delafontaine P. IGF-1 reduces inflammatory responses, suppresses oxidative stress, and decreases atherosclerosis progression in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2007;27:2684-2690. https://doi.org/10.1161/ATVBAHA.107.156257
  57. Nam SY, Lee EJ, Kim KR, Cha BS, Song YD, Lim SK, Lee HC, Huh KB. Effect of obesity on total and free insulin-like growth factor (IGF)-1, and their relationship to IGF-binding protein (BP)-1, IGFBP-2, IGFBP-3, insulin, and growth hormone. Int J Obes Relat Metab Disord. 1997;21:355-359. https://doi.org/10.1038/sj.ijo.0800412
  58. Weger N, Schlake T. Igf-I signalling controls the hair growth cycle and the differentiation of hair shafts. J Invest Dermatol. 2005;125:873-882. https://doi.org/10.1111/j.0022-202X.2005.23946.x
  59. Toyoshima KE, Asakawa K, Ishibashi N, Toki H, Ogawa M, Hasegawa T, Irie T, Tachikawa T, Sato A, Takeda A, Tsuji T. Fully functional hair follicle regeneration through the rearrangement of stem cells and their niches. Nat Commun. 2012;3:784. https://doi.org/10.1038/ncomms1784
  60. Rendl M, Polak L, Fuchs E. BMP signaling in dermal papilla cells is required for their hair follicle-inductive properties. Genes Dev. 2008;22:543-557. https://doi.org/10.1101/gad.1614408
  61. Zhou L, Yang K, Xu M, Andl T, Millar SE, Boyce S, Zhang Y. Activating ${\beta}$-catenin signaling in CD133-positive dermal papilla cells increases hair inductivity. FEBS J. 2016;283:2823-2835. https://doi.org/10.1111/febs.13784
  62. Huang CF, Chang YJ, Hsueh YY, Huang CW, Wang DH, Huang TC, Wu YT, Su FC, Hughes M, Chuong CM, Wu CC. Assembling composite dermal papilla spheres with adipose-derived stem cells to enhance hair follicle induction. Sci Rep. 2016;6:26436. https://doi.org/10.1038/srep26436

Cited by

  1. Stem Cell Aging in Lifespan and Disease: A State-of-the-Art Review vol.15, pp.None, 2020, https://doi.org/10.2174/1574888x15666200213105155
  2. Advanced Medical Therapies in the Management of Non-Scarring Alopecia: Areata and Androgenic Alopecia vol.21, pp.21, 2018, https://doi.org/10.3390/ijms21218390
  3. Could cold plasma act synergistically with allogeneic mesenchymal stem cells to improve wound skin regeneration in a large size animal model? vol.136, pp.None, 2018, https://doi.org/10.1016/j.rvsc.2021.01.019