Protective effects of human umbilical cord blood‑derived mesenchymal stem cells against dexamethasone‑induced apoptotic cell death in hair follicles

Bak,Dong   Ho; Lee,Esther; Choi,Mi   Ji; Lee,Byung   Chul; Kwon,Tae‑Rin; Kim,Jong‑Hwan; Jeon,Eun  Su; Oh,Wonil; Mun,Seog   Kyun; Park,Byung  Cheol; Na,Jungtae; Kim,Beom   Joon

doi:10.3892/ijmm.2019.4447

Protective effects of human umbilical cord blood‑derived mesenchymal stem cells against dexamethasone‑induced apoptotic cell death in hair follicles

Authors:
- Dong Ho Bak
- Esther Lee
- Mi Ji Choi
- Byung Chul Lee
- Tae‑Rin Kwon
- Jong‑Hwan Kim
- Eun Su Jeon
- Wonil Oh
- Seog Kyun Mun
- Byung Cheol Park
- Jungtae Na
- Beom Joon Kim
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Affiliations: Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, North Jeolla 56212, Republic of Korea, Department of Dermatology, College of Medicine, Seoul 06973, Republic of Korea, Biomedical Research Institute, R&D Center, MEDIPOST Co., Ltd., Seongnam, Gyeonggi 13494, Republic of Korea, Department of Otorhinolaryngology, College of Medicine, Chung‑Ang University, Seoul 06973, Republic of Korea, Department of Dermatology, Dankook Medical College, Cheonan, South Chungcheong 31116, Republic of Korea
Published online on: December 27, 2019 https://doi.org/10.3892/ijmm.2019.4447
Pages: 556-568
Copyright: © Bak et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Alopecia is a common and distressing condition, and developing new therapeutic agents to prevent hair loss is important. Human umbilical cord blood‑derived mesenchymal stem cells (hUCB‑MSCs) have been studied intensively in regenerative medicine. However, the therapeutic potential of these cells against hair loss and hair organ damage remains unclear, and the effects of hUCB‑MSC transplantation on hair loss require evaluation. The current study aimed to investigate the effects of hUCB‑MSCs on hair regression in vivo and restoration of anagen conduction on hair growth in vitro. The effects of hUCB‑MSCs were explored in mouse catagen induction models using a topical treatment of 0.1% dexamethasone to induce hair regression. Dexamethasone was also used to simulate a stress environment in vitro. The results demonstrated that hUCB‑MSCs significantly prevented hair regression induced by dexamethasone topical stimulation in vivo. Additionally, hUCB‑MSCs significantly increased the proliferation of human dermal papilla cells (hDPCs) and HaCaT cells, which are key constituent cells of the hair follicle. Stimulation of vascular endothelial growth factor secretion and decreased expression of DKK‑1 by hUCB‑MSCs were also observed in hDPCs. Restoration of cell viability by hUCB‑MSCs suggested that these cells exerted a protective effect on glucocorticoid stress‑associated hair loss. In addition, anti‑apoptotic effects and regulation of the autophagic flux recovery were observed in HaCaT cells. The results of the present study indicated that hUCB‑MSCs may have the capacity to protect hair follicular dermal papilla cells and keratinocytes, thus preventing hair loss. Additionally, the protective effects of hUCB‑MSCs may be resistant to dysregulation of autophagy under harmful stress.

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1	Ding DC, Chang YH, Shyu WC and Lin SZ: Human umbilical cord mesenchymal stem cells: A new era for stem cell therapy. Cell Transplant. 24:339–347. 2015. View Article : Google Scholar : PubMed/NCBI
2	Oh W, Kim DS, Yang YS and Lee JK: Immunological properties of umbilical cord blood-derived mesenchymal stromal cells. Cell Immunol. 251:116–123. 2008. View Article : Google Scholar : PubMed/NCBI
3	Chen M, Xiang Z and Cai J: The anti-apoptotic and neuro-protective effects of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) on acute optic nerve injury is transient. Brain Res. 1532:63–75. 2013. View Article : Google Scholar : PubMed/NCBI
4	Kang SG, Jeun SS, Lim JY, Kim SM, Yang YS, Oh WI, Huh PW and Park CK: Cytotoxicity of human umbilical cord blood-derived mesenchymal stem cells against human malignant glioma cells. Child's Nerv Syst. 24:293–302. 2008. View Article : Google Scholar
5	Lim JY, Jeong CH, Jun JA, Kim SM, Ryu CH, Hou Y, Oh W, Chang JW and Jeun SS: Therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of cerebral ischemia. Stem Cell Res Ther. 2:382011. View Article : Google Scholar : PubMed/NCBI
6	Kim JY, Jeon HB, Yang YS, Oh W and Chang JW: Application of human umbilical cord blood-derived mesenchymal stem cells in disease models. World J Stem Cells. 2:34–38. 2010. View Article : Google Scholar
7	Chung JY, Song M, Ha CW, Kim JA, Lee CH and 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. 5:392014. View Article : Google Scholar : PubMed/NCBI
8	Hillmer AM, Hanneken S, Ritzmann S, Becker T, Freudenberg J, Brockschmidt FF, Flaquer A, Freudenberg-Hua Y, Jamra RA, Metzen C, et al: Genetic variation in the human androgen receptor gene is the major determinant of common early-onset androgenetic alopecia. Am J Hum Genet. 77:140–148. 2005. View Article : Google Scholar : PubMed/NCBI
9	Lindner G, Botchkarev VA, Botchkareva NV, Ling G, van der Veen C and Paus R: Analysis of apoptosis during hair follicle regression (catagen). Am J Pathol. 151:16011997.PubMed/NCBI
10	Courtois M, Loussouarn G, Hourseau C and Grollier JF: Hair cycle and alopecia. Skin Pharmacol. 7:84–89. 1994. View Article : Google Scholar : PubMed/NCBI
11	Silverman MN and Sternberg EM: Glucocorticoid regulation of inflammation and its functional correlates: From HPA axis to glucocorticoid receptor dysfunction. Ann N Y Acad Sci. 1261:55–63. 2012. View Article : Google Scholar : PubMed/NCBI
12	Pérez P: Glucocorticoid receptors, epidermal homeostasis and hair follicle differentiation. Dermatoendocrinol. 3:166–174. 2011. View Article : Google Scholar : PubMed/NCBI
13	Slominski A, Wortsman J, Tuckey RC and Paus R: Differential expression of HPA axis homolog in the skin. Mol Cell Endocrinol. 265:143–149. 2007. View Article : Google Scholar : PubMed/NCBI
14	Zhang X, Yu M, Yu W, Weinberg J, Shapiro J and McElwee KJ: Development of alopecia areata is associated with higher central and peripheral hypothalamic-pituitary-adrenal tone in the skin graft induced C3H/HeJ mouse model. J Invest Dermatol. 129:1527–1538. 2009. View Article : Google Scholar
15	Ito N, Ito T, Kromminga A, Bettermann A, Takigawa M, Kees F, Straub RH and Paus R: Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize cortisol. FASEB J. 19:1332–1334. 2005. View Article : Google Scholar : PubMed/NCBI
16	Arck PC, Handjiski B, Hagen E, Joachim R, Klapp BF and Paus R: Indications for a 'brain-hair follicle axis (BHA)': Inhibition of keratinocyte proliferation and up-regulation of keratinocyte apoptosis in telogen hair follicles by stress and substance P. FASEB J. 15:2536–2538. 2001. View Article : Google Scholar : PubMed/NCBI
17	Albus U: Guide for the Care and Use of Laboratory Animals. 8th edition. SAGE Publications; Sage UK, London: 2012
18	Kwon TR, Kim JH, Hong JY, Seok J, Kim JM, Bak DH, Choi MJ, Mun SK, Kim CW and Kim BJ: Irradiation with 310 nm and 340 nm ultraviolet light-emitting-diodes can improve atopic dermatitis-like skin lesions in NC/Nga mice. Photochem Photobiol Sci. 17:1127–1135. 2018. View Article : Google Scholar : PubMed/NCBI
19	Crema A, Ledda M, Fioretti D, Lolli MG, Sanchez M, Carico E, Marchese R, Rinaldi M and Lisi A: Combination of cord blood-derived human hepatic progenitors and hepatogenic factors strongly improves recovery after acute liver injury in mice through modulation of the Wnt/β-catenin signaling. J Tissue Eng Regen Med. 13:1031–1043. 2019.PubMed/NCBI
20	Park S, Erdogan S, Hwang D, Hwang S, Han EH and Lim YH: Bee venom promotes hair growth in association with inhibiting 5α-reductase expression. Biol Pharm Bull. 39:1060–1068. 2016. View Article : Google Scholar : PubMed/NCBI
21	Müller-Röver S, Handjiski B, van der Veen C, Eichmüller S, Foitzik K, McKay IA, Stenn KS and Paus R: A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages. J Invest Dermatol. 117:3–15. 2001. View Article : Google Scholar : PubMed/NCBI
22	Choi W, Kwon SJ, Jin HJ, Jeong SY, Choi SJ, Oh W, Yang YS, Jeon HB and Jeon ES: Optimization of culture conditions for rapid clinical-scale expansion of human umbilical cord blood-derived mesenchymal stem cells. Clin Transl Med. 6:382017. View Article : Google Scholar : PubMed/NCBI
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
24	Bjørkøy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, Stenmark H and Johansen T: P62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol. 171:603–614. 2005. View Article : Google Scholar : PubMed/NCBI
25	Lippai M and Lőw P: The role of the selective adaptor p62 and ubiquitin-like proteins in autophagy. BioMed Res Int. 2014:8327042014. View Article : Google Scholar : PubMed/NCBI
26	Lachgar S, Charveron M, Gall Y and Bonafe J: Minoxidil upregulates the expression of vascular endothelial growth factor in human hair dermal papilla cells. Br J Dermatol. 138:407–411. 1998. View Article : Google Scholar : PubMed/NCBI
27	Ito M, Yang Z, Andl T, Cui C, Kim N, Millar SE and Cotsarelis G: Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature. 447:316–320. 2007. View Article : Google Scholar : PubMed/NCBI
28	Chen Y and Yu L: Autophagic lysosome reformation. Exp Cell Res. 319:142–146. 2013. View Article : Google Scholar
29	Young TH, Lee CY, Chiu HC, Hsu CJ and Lin SJ: Self-assembly of dermal papilla cells into inductive spheroidal microtissues on poly (ethylene-co-vinyl alcohol) membranes for hair follicle regeneration. Biomaterials. 29:3521–3530. 2008. View Article : Google Scholar : PubMed/NCBI
30	Sennett R and Rendl M: Mesenchymal-epithelial interactions during hair follicle morphogenesis and cycling. Semi Cell Dev Biol. 23:917–927. 2012. View Article : Google Scholar
31	Yoo BY, Shin YH, Yoon HH, Seo YK, Song KY and Park JK: Application of mesenchymal stem cells derived from bone marrow and umbilical cord in human hair multiplication. J Dermatolol Sci. 60:74–83. 2010. View Article : Google Scholar
32	Kim Y, Jin HJ, Heo J, Ju H, Lee HY, Kim S, Lee S, Lim J, Jeong SY, Kwon J, et al: Small hypoxia-primed mesenchymal stem cells attenuate graft-versus-host disease. Leukemia. 32:26722018. View Article : Google Scholar : PubMed/NCBI
33	Shin H, Ryu HH, Kwon O, Park BS and 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. 54:730–735. 2015. View Article : Google Scholar : PubMed/NCBI
34	Hocking AM and Gibran NS: Mesenchymal stem cells: Paracrine signaling and differentiation during cutaneous wound repair. Exp Cell Res. 316:2213–2219. 2010. View Article : Google Scholar : PubMed/NCBI
35	Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, Salto-Tellez M, Timmers L, Lee CN, El Oakley RM, et al: Exosome secreted by MSC reduces myocardial ischemia/reper-fusion injury. Stem Cell Res. 4:214–222. 2010. View Article : Google Scholar : PubMed/NCBI
36	Paus R, Handjiski B, Czarnetzki BM and Eichmüller S: A murine model for inducing and manipulating hair follicle regression (catagen): Effects of dexamethasone and cyclosporin A. J Invest Dermatol. 103:143–147. 1994. View Article : Google Scholar : PubMed/NCBI
37	Kwack MH, Lee JH, Seo CH, Kim JC, Kim MK and Sung YK: Dickkopf-1 is involved in dexamethasone-mediated hair follicle regression. Exp Dermatol. 26:952–954. 2017. View Article : Google Scholar : PubMed/NCBI
38	Premanand A and Rajkumari BR: Androgen modulation of Wnt/β-catenin signaling in androgenetic alopecia. Arch Dermatol Res. 310:1–9. 2018. View Article : Google Scholar
39	Kishimoto J, Burgeson RE and Morgan BA: Wnt signaling maintains the hair-inducing activity of the dermal papilla. Genes Dev. 14:1181–1185. 2000.PubMed/NCBI
40	Huelsken J, Vogel R, Erdmann B, Cotsarelis G and Birchmeier W: β-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell. 105:533–545. 2001. View Article : Google Scholar : PubMed/NCBI
41	Iida M, Ihara S and Matsuzaki T: Hair cycle-dependent changes of alkaline phosphatase activity in the mesenchyme and epithelium in mouse vibrissal follicles. Dev Growth Differ. 49:185–195. 2007. View Article : Google Scholar : PubMed/NCBI
42	Zhou L, Xu M, Yang Y, Yang K, Wickett RR, Andl T, Millar SE and Zhang Y: Activation of β-catenin signaling in CD133-positive dermal papilla cells drives postnatal hair growth. Plos One. 11:e01604252016. View Article : Google Scholar
43	He J, Zhou J, Yang W, Zhou Q, Liang X, Pang X, Li J, Pan F and Liang H: Dexamethasone affects cell growth/apoptosis/chemo-sensitivity of colon cancer via glucocorticoid receptor α/NF-κB. Oncotarget. 8:67670–67683. 2017.PubMed/NCBI
44	Boix J, Bigas J, Sevilla LM, Iacobone M, Citton M, Torresan F, Caroccia B, Rossi GP and Pérez P: Primary aldosteronism patients show skin alterations and abnormal activation of glucocorticoid receptor in keratinocytes. Sci Rep. 7:158062017. View Article : Google Scholar : PubMed/NCBI
45	Deckers J, Bougarne N, Mylka V, Desmet S, Luypaert A, Devos M, Tanghe G, Van Moorleghem J, Vanheerswynghels M, De Cauwer L, et al: Co-Activation of glucocorticoid receptor and peroxisome proliferator-activated receptor-γ in murine skin prevents worsening of atopic march. J Invest Dermatol. 138:1360–1370. 2018. View Article : Google Scholar
46	Gauthier A, Fisch A, Seuwen K, Baumgarten B, Ruffner H, Aebi A, Rausch M, Kiessling F, Bartneck M, Weiskirchen R, et al: Glucocorticoid-loaded liposomes induce a pro-resolution phenotype in human primary macrophages to support chronic wound healing. Biomaterials. 178:481–495. 2018. View Article : Google Scholar : PubMed/NCBI
47	Vogt CJ and Schmid-Schönbein GW: Microvascular endothelial cell death and rarefaction in the glucocorticoid-induced hypertensive rat. Microcirculation. 8:129–139. 2001. View Article : Google Scholar : PubMed/NCBI
48	Llambi F and Green DR: Apoptosis and oncogenesis: Give and take in the BCL-2 family. Curr Opin Genet Dev. 21:12–20. 2011. View Article : Google Scholar : PubMed/NCBI
49	Czabotar PE, Lessene G, Strasser A and Adams JM: Control of apoptosis by the BCL-2 protein family: Implications for physiology and therapy. Nat Rev Mol Cell Biol. 15:492014. View Article : Google Scholar
50	Palikaras K, Lionaki E and Tavernarakis N: Balancing mitochondrial biogenesis and mitophagy to maintain energy metabolism homeostasis. Cell Death Differ. 22:1399–1401. 2015. View Article : Google Scholar : PubMed/NCBI
51	Crotzer VL and Blum JS: Autophagy and adaptive immunity. Immunology. 131:9–17. 2010.PubMed/NCBI
52	Levine B and Deretic V: Unveiling the roles of autophagy in innate and adaptive immunity. Nat Rev Immunol. 7:767–777. 2007. View Article : Google Scholar : PubMed/NCBI
53	Parodi C, Hardman JA, Allavena G, Marotta R, Catelani T, Bertolini M, Paus R and Grimaldi B: Autophagy is essential for maintaining the growth of a human (mini-) organ: Evidence from scalp hair follicle organ culture. Plos Biol. 16:e20028642018. View Article : Google Scholar
54	Jiang P and Mizushima N: LC3-and p62-based biochemical methods for the analysis of autophagy progression in mammalian cells. Methods. 75:13–18. 2015. View Article : Google Scholar
55	Wurzer B, Zaffagnini G, Fracchiolla D, Turco E, Abert C, Romanov J and Martens S: Oligomerization of p62 allows for selection of ubiquitinated cargo and isolation membrane during selective autophagy. Elife. 4:e089412015. View Article : Google Scholar : PubMed/NCBI