Prevention of irradiation-induced damage to salivary glands by local delivery of adipose-derived stem cells via hyaluronic acid-based hydrogels

Eun-Jae Chung; Ji Suk Choi; Jisoo Shin; Ha-Na Cho; Suyeon Kim; Ji Yong Park; Yun-sang Lee; Yong-il Kim; Hong-Gyun Wu; Seung-Woo Ch; Seong Keun Kwon

Journal of Industrial and Engineering Chemistry, Vol.90, 47-57, October, 2020

DOI10.1016/j.jiec.2020.06.014 Export Citation

Prevention of irradiation-induced damage to salivary glands by local delivery of adipose-derived stem cells via hyaluronic acid-based hydrogels

Eun-Jae Chung^{1, 2}, Ji Suk Choi³, Jisoo Shin⁴, Ha-Na Cho³, Suyeon Kim³, Ji Yong Park^{5, 6}, Yun-sang Lee⁶, Yong-il Kim⁷, Hong-Gyun Wu⁸, Seung-Woo Ch^{4, †}, and Seong Keun Kwon^{1, 2, †}

¹Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
²Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Republic of Korea
³Department of Otorhinolaryngology-Head and Neck Surgery, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
⁴Department of Biotechnology, Yonsei University, Seoul, Republic of Korea
⁵Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea
⁶Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
⁷Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
⁸Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea

E-mail:,

Most patients with head and neck cancer experience salivary gland dysfunction after chemo- and radiotherapies. There is currently no available treatment for this condition. Intervention with stem cell therapy has emerged as a promising approach. Although some progress has been made with systemic delivery of stem cells, it remains challenging to deliver a sufficient number of stem cells to the damaged tissue. Furthermore, local delivery of stem cells involves frequent cell loss. Herein, we evaluated the ability of adipose-derived stem cells (ASCs) with or without hydrogel to prevent salivary gland damage. Salivary gland cells were isolated from irradiated mouse submandibular glands. These cells exhibited higher expression levels of amylase, mucin, and aquaporin-5 when co-cultured with ASCs. Local delivery of ASCs into the salivary gland, using in situ-forming hyaluronic acid-based hydrogel (HA gel) as a carrier, revealed that ASCs remained at the injection site for a longer duration, compared with ASCs that were injected without HA gel. The salivary gland exhibited better function and morphology when ASCs were injected using an HA gel. In conclusion, retention of locally delivered ASCs by HA gels can enhance the paracrine effect of ASCs, thereby preventing irradiation-induced damage to the salivary gland and subsequent dysfunction.

Keywords:Irradiation-induced damage;Salivary gland;Adipose-derived stem cells;Hyaluronic acid-based hydrogel;Local delivery

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[Referenced By]

[1] Grundmann O, Mitchell GC, Limesand KH, J. Dent. Res., 88, 894 (2009)

[2] Jensen SB, Pedersen AML, Vissink A, Andersen E, Brown CG, Davies AN, et al., Support Care Cancer, 18, 1039 (2010)

[3] Pinna R, Campus G, Cumbo E, Mura I, Milia E, Ther. Clin. Risk Manag., 11, 171 (2015)

[4] Turner MD, Dent. Clin. North Am., 60, 435 (2016)

[5] Cassolato SF, Turnbull RS, Gerodontol, 20, 64 (2003)

[6] Guggenheimer J, Moore PA, J. Am. Dent. Assoc., 134, 61 (2003)

[7] Wynn RL, Meiller TF, Gen. Dent., 48, 630 (2000)

[8] Jacobs CD, Pas M, Oncology, 10, 16 (1996)

[9] Daniels TE, Wu AJ, J. Calif. Dent. Assoc., 28, 933 (2000)

[10] Nicolay NH, Perez RL, Saffrich R, Huber PE, Oncotarget, 6, 19366 (2015)

[11] Huang CK, Lee SO, Luo J, Wang R, Dang Q, Chang C, Methods Mol. Biol., 1213, 69 (2014)

[12] Nicolay NH, Perez RL, Debus J, Huber PE, Cancer Lett., 366, 133 (2015)

[13] Sen A, Lea-Currie YR, Sujkowska D, Franklin DM, Wilkison WO, Halvorsen YDC, Gimble JM, J. Cell. Biochem., 81, 312 (2001)

[14] Jeong J, Baek H, Kim YJ, Choi Y, Lee H, Lee E, Kim ES, Hah JH, Kwon TK, Choi IJ, Kwon H, Exp. Mol. Med., 45, e58 (2013)

[15] Sumita Y, Liu Y, Khalili S, Maria OM, Xia D, Key S, Cotrim AP, Mezey E, Tran SD, Int. J. Biochem. Cell Biol., 43, 80 (2011)

[16] Xiong X, Shi X, Chen F, Int. J. Mol. Med., 34, 749 (2014)

[17] Lin CY, Chang FH, Chen CY, Huang CY, Hu FC, Huang WK, Ju SS, Chen MH, J. Dent. Res., 90, 341 (2011)

[18] Kojima T, Kanemaru S, Hirano S, Tateya I, Ohno S, Nakamura T, Laryngoscope, 121, 1864 (2011)

[19] Lim JY, Yi TG, Choi JS, Jang YH, Lee S, Kim HJ, Song SU, Kim YM, Oral Oncol., 49, 136 (2013)

[20] Lim JY, Ra JC, Shin IS, Jang YH, An HY, Choi JS, Kim WC, Kim YM, PLoS ONE, 8, e71167 (2013)

[21] Lombaert I, Moveahednia MM, Adine C, Ferreira JN, Stem Cells, 35, 97 (2017)

[22] Shin J, Lee JS, Lee C, Park HJ, Yang K, Jin Y, Ryu JH, Hong KS, Moon SH, Chung HM, Yang HS, Um SH, Oh JW, Kim DI, Lee H, Cho SW, Adv. Funct. Mater., 25(25), 3814 (2015)

[23] Pringle S, Nandur LSY, Marianne Z, Ronald O, Coppes RP, J. Vis. Exp, 48, e2484 (2011)

[24] Murray LA, Kramer MS, Hesson DP, Watkins BA, Fey EG, Argentieri RL, Shaheen F, Knight DA, Sonis ST, Fibrogenesis Tissue Rep., 3, 11 (2010)

[25] Peters SB, Naim N, Nelson DA, Mosier AP, Cady NC, Larsen M, Tissue Eng. A, 20, 1632 (2014)

[26] Mosier AP, Peters SB, Larsen M, Cady NC, Biosensors, 4, 18 (2014)

[27] Park KM, Park KD, Encycl. Polym. Sci. Technol. (2017).

[28] Choi SH, Hong ZY, Nam JK, Lee HJ, Jang J, Yoo RJ, Lee YJ, Lee CY, Kim KH, et al., Clin. Cancer Res., 21, 3716 (2015)

[29] Acauan MD, Figueiredo MAZ, Cherubini K, Gomes APN, Salum FG, Arch. Oral Biol., 60, 1802 (2015)

[30] Lee DE, Ayoub N, Agrawal DK, Stem Cell Res. Ther., 7, 37 (2016)

[31] Salgado AJ, Reis RL, Sousa NJ, Gimble JM, Curr. Stem Cell Res. Ther., 5, 103 (2010)

[32] Burdick JA, Prestwich GD, Adv. Mater., 23, 41 (2011)

[33] Li WW, Talcott KE, Zhai AW, Kruger EA, Li VW, Adv. Skin Wound Care, 18, 491 (2005)

[34] Nacu N, Luzina IG, Highsmith K, Lockatell V, Pochetuhen K, Cooper ZA, Gillmeister MP, Todd NW, Atamas SP, J. Immunol., 180, 5036 (2008)

[35] McDonald PP, Fedok VA, Bratton D, Henson PM, J. Immunol., 163, 6164 (1999)

[36] Fornetti J, Flanders KC, Henson PM, Tan AC, Borges VF, Schedin P, Cell Death Differ., 23, 185 (2016)