Browse > Article
http://dx.doi.org/10.4062/biomolther.2018.195

Udenafil Induces the Hair Growth Effect of Adipose-Derived Stem Cells  

Choi, Nahyun (College of Pharmacy, Yonsei University)
Sung, Jong-Hyuk (College of Pharmacy, Yonsei University)
Publication Information
Biomolecules & Therapeutics / v.27, no.4, 2019 , pp. 404-413 More about this Journal
Abstract
Udenafil, which is a $PDE_5$ inhibitor, is used to treat erectile dysfunction. However, it is unclear whether udenafil induces hair growth via the stimulation of adipose-derived stem cells (ASCs). In this study, we investigated whether udenafil stimulates ASCs and whether increased growth factor secretion from ASCs to facilitate hair growth. We found that subcutaneous injection of udenafiltreated ASCs accelerated telogen-to-anagen transition in vivo. We also observed that udenafil induced proliferation, migration and tube formation of ASCs. It also increased the secretion of growth factors from ASCs, such as interleukin-4 (IL-4) and IL12B, and the phosphorylation of ERK1/2 and $NF{\kappa}B$. Furthermore, concomitant upregulation of IL-4 and IL12B mRNA levels was attenuated by ERK inhibitor or $NF{\kappa}B$ knockdown. Application of IL-4 or IL12B enhanced anagen induction in mice and increased hair follicle length in organ culture. The results indicated that udenafil stimulates ASC motility and increases paracrine growth factor, including cytokine signaling. Udenafil-stimulated secretion of cytokine from ASCs may promote hair growth via the ERK and $NF{\kappa}B$ pathways. Therefore, udenafil can be used as an ASC-preconditioning agent for hair growth.
Keywords
Udenafil; Adipose-derived stem cells; IL-4; IL12B; Hair growth;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Gopal, V. K., Francis. S. H. and Corbin, J. D. (2001) Allosteric sites of phosphodiesterase-5 (PDE5). A potential role in negative feedback regulation of cGMP signaling in corpus cavernosum. Eur. J. Biochem. 268, 3304-3312.   DOI
2 Gregoriou, S., Papafragkaki, D., Kontochristopoulos, G., Rallis, E., Kalogeromitros, D. and Rigopoulos, D. (2010) Cytokines and other mediators in alopecia areata. Mediators Inflamm. 2010, 928030.   DOI
3 Groves, R. W., Williams, I. R., Sarkar, S., Nakamura, K. and Kupper, T. S. (1994) Analysis of epidermal IL-1 family members in vivo using transgenic mouse models. J. Investig. Dermatol. 102, 556.
4 Buhl, A. E., Waldon, D. J., Kawabe, T. T. and Holland, J. M. (1989) Minoxidil stimulates mouse vibrissae follicles in organ culture. J. Dermatol. Sci. 92, 315-320.
5 Han, J. H., Kwon, O. S., Chung, J. H., Cho, K. H., Eun, H. C. and Kim, K. H. (2004) Effect of minoxidil on proliferation and apoptosis in dermal papilla cells of human hair follicle. J. Dermatol. Sci. 34, 91-98.   DOI
6 Headington, J. T. (1987) Hair follicle biology and topical minoxidil: possible mechanisms of action. Dermatologica 175, 19-22.   DOI
7 Hoffmann, R. T. (1999) The potential role of cytokines and T cells in alopecia areata. J. Investig. Dermatol. Symp. Proc. 4, 235-238.   DOI
8 Hoffmann, R. and Happle, R. (1995) Does interleukin-1 induce hair loss? Dermatology 191, 273-275.   DOI
9 Jeong, H. H., Piao, S., Ha, J. N., Kim, I. G., Oh, S. H., Lee, J. H., Cho, H. J., Hong, S. H., Kim, S. W. and Lee, J. Y. (2013a) Combined therapeutic effect of udenafil and adipose-derived stem cell (ADSC)/brain-derived neurotrophic factor (BDNF)-membrane system in a rat model of cavernous nerve injury. Urology 81, 1108.e7-1108.e14.   DOI
10 Hoke, N. N., Salloum, F. N., Kass, D. A., Das, A. and Kukreja, R. C. (2012) Preconditioning by phosphodiesterase-5 inhibition improves therapeutic efficacy of adipose-derived stem cells following myocardial infarction in mice. Stem Cells 30, 326-335.   DOI
11 Jeong, Y. M., Sung, Y. K., Kim, W. K., Kim, J. H., Kwack, M. H., Yoon, I., Kim, D. D. and Sung, J. H. (2013b) Ultraviolet B preconditioning enhances the hair growth-promoting effects of adipose-derived stem cells via generation of reactive oxygen species. Stem Cells Dev. 22, 158-168.   DOI
12 Jin, S. E. and Sung, J. H. (2016) Hair regeneration using adiposederived stem cells. Histol. Histopathol. 31, 249-256.
13 Kang, K. K., Choi, S. M., Ahn, G. J., Kwon, J. W. and Kim, W. B. (2004) The effect of DA-8159 oncorpus cavernosal smooth muscle relaxation and penile erection in diabetic rabbits. Urol. Res. 32, 107-111.   DOI
14 Kwack, M. H., Kang, B. M., Kim, M. K., Kim, J. C. and Sung, Y. K. (2011) Minoxidil activates beta-catenin pathway in human dermal papilla cells: a possible explanation for its anagen prolongation effect. J. Dermatol. Sci. 62, 154-159.   DOI
15 Kim, J. H., Kim, W. K., Sung, Y. K., Kwack, M. H., Song, S. Y., Choi, J. S., Park, S. G., Yi, T., Lee, H. J., Kim, D. D., Seo, H. M., Song, S. U. and Sung, J. H. (2014a) The molecular mechanism underlying the proliferating and preconditioning effect of vitamin C on adiposederived stem cells. Stem Cells Dev. 23, 1364-1376.   DOI
16 Kim, J. H., Park, S. G., Kim, W. K., Song, S. U. and Sung, J. H. (2015) Functional regulation of adipose-derived stem cells by PDGFD. Stem Cells 33, 542-556.   DOI
17 Kim, J. H., Park, S. H., Park, S. G., Choi, J. S., Xia, Y. and Sung, J. H. (2011) The pivotal role of reactive oxygen species generation in the hypoxia-induced stimulation of adipose-derived stem cells. Stem Cells Dev. 20, 1753-1761.   DOI
18 Kim, W. S., Han, L., Hwang, S. J., Sung, J. H. (2014b) An update on niche composition, signaling and functional regulation of adiposederived stem cell. Expert Opin. Biol. Ther. 14, 1091-1102.   DOI
19 Kim, W. S., Park, B. S., Sung, J. H., Yang, J. M., Park, S. B., Kwak, S. J. and Park, J. S. (2007) Wound healing effect of adipose-derived stem cells: a critical role of secretory factors on human dermal fibroblasts. J. Dermatol. Sci. 48, 15-24.   DOI
20 Lee, C. H., Kim, H. S., Goo, M. J., Kang, K. K., Ahn, B. O., Kim, S. H. and Yang D. Y. (2011) Chronic administration of udenafil, a selective phosphodiesterase type 5 inhibitor, promotes erectile function recovery in an animal model of bilateral cavernous nerve crush injury. J. Sex Med. 8, 1330-1340.   DOI
21 Pyriochou, A., Zhou, Z., Koika, V., Petrou, C., Cordopatis, P., Sessa, W. C. and Papapetropoulos, A. (2007) The phosphodiesterase 5 inhibitor sildenafil stimulates angiogenesis through a protein kinase G/MAPK pathway. J. Cell. Physiol. 211, 197-204.   DOI
22 Mandt, N., Geilen, C. C., Wrobel, A., Gelber, A., Kamp, H., Orfanos, C. E. and Blume-Peytavi, U. (2002) Interleukin-4 induces apoptosis in cultured human follicular keratinocytes, but not in dermal papilla cells. Eur. J. Dermatol. 12, 432-438.
23 Michelet, J. F., Commo, S., Billoni, N., Mahe, Y. F. and Bernard, B. A. (1997) Activation of cytoprotective prostaglandin synthase-1 by minoxidil as a possible explanation for its hair growth-stimulating effect. J. Invest. Dermatol. 108, 205-209.   DOI
24 Otomo, S. (2002) Hair growth effect of minoxidil. Nihon Yakurigaku Zasshi 119, 167-74.   DOI
25 Paick, J. S., Kim, S. W., Park, Y. K., Hyun, J. S., Park, N. C., Lee, S. W., Park, K., Moon, K. H. and Chung, W. S. (2009) The efficacy and safety of udenafil [Zydena] for the treatment of erectile dysfunction in hypertensive men taking concomitant antihypertensive agents. J. Sex Med. 6, 3166-3176.   DOI
26 Perez-Meza, D., Ziering, C., Sforza, M., Krishnan, G., Ball, E. and Daniels, E. (2017) Hair follicle growth by stromal vascular fractionenhanced adipose transplantation in baldness. Stem Cells Cloning 10, 1-10.   DOI
27 Ramot, Y., Marzani, B., Pinto, D., Sorbellini, E. and Rinaldi, F. (2018) IL-17 inhibition: is it the long-awaited savior for alopecia areata? Arch. Dermatol. Res. 310, 383-390.   DOI
28 Li, M., Marubayashi, A., Nakaya, Y., Fukui, K. and Arase, S. (2001) Minoxidil-induced hair growth is mediated by adenosine in cultured dermal papilla cells: possible involvement of sulfonylurea receptor 2B as a target of minoxidil. J. Invest. Dermatol. 117, 1594-1600.   DOI
29 Sahara, M., Sata, M., Morita, T., Nakajima. T., Hirata, Y. and Nagai, R. (2010) A phosphodiesterase-5 inhibitor vardenafil enhances angiogenesis through a protein kinase G-dependent hypoxia-inducible factor-1/vascular endothelial growth factor pathway. Arterioscler. Thromb. Vasc. Biol. 30, 1315-1324.   DOI
30 Redler, S., Albert, F., Brockschmidt, F. F., Herold, C., Hanneken, S., Eigelshoven, S., Giehl, K. A., Kruse, R., Lutz, G., Wolff, H., Blaumeiser, B., Bohm, M., Becker, T., Nothen, M. M. and Betz, R. C. (2012) Investigation of selected cytokine genes suggests that IL- 2RA and the TNF/LTA locus are risk factors for severe alopecia areata. Br. J. Dermatol. 167, 1360-1365.   DOI
31 Won, C. H., Yoo, H. G., Kwon, O. S., Sung, M. Y, Kang, Y. J., Chung, J. H., Park, B. S., Sung, J. H., Kim, W. S. and Kim, K. H. (2010) Hair growth promoting effects of adipose tissue-derived stem cells. J. Dermatol. Sci. 57, 134-137.   DOI
32 Yang, Y., Choi, H., Seon, M., Cho, D. and Bang, S. I. (2016) LL-37 stimulates the functions of adipose-derived stromal/stem cells via early growth response 1 and the MAPK pathway. Stem Cell Res. Ther. 7, 58.   DOI
33 Yi, T., Kim, W. K., Choi, J. S., Song, S. Y., Han, J., Kim, J. H., Kim, W. S., Park, S. G., Lee, H. J., Cho, Y. K., Hwang, S. J., Song, S. U. and Sung, J. H. (2014) Isolation of adipose-derived stem cells by using a subfractionation culturing method. Expert Opin. Biol. Ther. 14, 1551-1560.   DOI
34 Dhayade, S., Kaesler, S, Sinnberg, T., Dobrowinski, H., Peters, S., Naumann, U., Liu, H., Hunger, R. E., Thunemann, M., Biedermann, T., Schittek, B., Simon, H. U., Feil, S. and Feil, R. (2016) Sildenafil Potentiates a cGMP-Dependent Pathway to Promote Melanoma Growth. Cell Rep. 14, 2599-2610.   DOI
35 Ackermann, L. W. and Denning, G. M. (2004) Nuclear factor-kappaB contributes to interleukin-4- and interferon-dependent polymeric immunoglobulin receptor expression in human intestinal epithelial cells. Immunology 111, 75-85.   DOI
36 Bao, K. and Reinhardt, R. L. (2015) The differential expression of IL-4 and IL-13 and its impact on type-2 immunity. Cytokine 75, 25-37.   DOI
37 Bunnell, B. A., Estes, B. T., Guilak, F. and Gimble, J. M. (2008) Differentiation of adipose stem cells. Methods Mol. Biol. 456, 155-171.   DOI
38 Celik, S. D. and Ates, O. (2018) Genetic analysis of interleukin 18 gene polymorphisms in alopecia areata. J. Clin. Lab. Anal. 32, e22386.   DOI
39 Choi, N., Shin, S., Song, S. U. and Sung, J. H. (2018) Minoxidil promotes hair growth through stimulation of growth factor release from adipose-derived stem cells. Int. J. Mol. Sci. 19, E691.   DOI
40 Festa, E., Fretz, J., Berry, R., Schmidt, B., Rodeheffer, M., Horowitz, M. and Horsley, V. (2011) Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling. Cell 146, 761-771.   DOI