Intraprostatic injection of exosomes isolated from adipose-derived mesenchymal stem cells for the treatment of chronic non-bacterial prostatitis
Farjam Goudarzi
Regenerative Medicine Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
Search for more papers by this authorAmir Kiani
Regenerative Medicine Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
Search for more papers by this authorMahmoudreza Moradi
Regenerative Medicine Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
Department of Urology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
Search for more papers by this authorBabak Haghshenas
Regenerative Medicine Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
Search for more papers by this authorMohammad Hashemnia
Department of Pathobiology, Faculty of Veterinary Medicine, Razi University, Kermanshah, Iran
Search for more papers by this authorAfshin Karami
Regenerative Medicine Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
Search for more papers by this authorCorresponding Author
Adel Mohammadalipour
Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
Correspondence
Adel Mohammadalipour, Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
Email: [email protected]
Search for more papers by this authorFarjam Goudarzi
Regenerative Medicine Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
Search for more papers by this authorAmir Kiani
Regenerative Medicine Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
Search for more papers by this authorMahmoudreza Moradi
Regenerative Medicine Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
Department of Urology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
Search for more papers by this authorBabak Haghshenas
Regenerative Medicine Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
Search for more papers by this authorMohammad Hashemnia
Department of Pathobiology, Faculty of Veterinary Medicine, Razi University, Kermanshah, Iran
Search for more papers by this authorAfshin Karami
Regenerative Medicine Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
Search for more papers by this authorCorresponding Author
Adel Mohammadalipour
Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
Correspondence
Adel Mohammadalipour, Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
Email: [email protected]
Search for more papers by this authorAbstract
Mesenchymal stem cells (MSCs) own the capacity to secrete trophic factors as exosomes which play significant roles in regulating the functions of other cells and preventing inflammation. Due to the inflammatory process in chronic non-bacterial prostatitis (CNP) and the ambiguity in the treatment of this disease, the present study was aimed to investigate the therapeutic use of adipose-derived MSC exosomes in an animal model of CNP. MSCs were first isolated from rat subcutaneous adipose tissue, and exosomes were extracted from them. Specific features of exosomes were characterized by a scanning electron microscope, western blot technique, and Dynamic Light Scattering methods. To establish CNP in rats, intraprostatic injection of Freund's complete adjuvant was done. After confirmation of prostatitis, intraprostatic injections of exosomes were performed for treatment. Histological evaluation revealed that treatment with exosomes resulted in a relative improvement of lesions caused by CNP. The expression of p-NF-κB and p-IκBα proteins along with inflammatory markers was significantly increased in the CNP group, which treatment with exosomes significantly reduced their expression as well as IL-1β and TNF-α proteins. The antioxidant effects of exosomes were also determined by significantly regulating glutathione peroxidase and superoxide dismutase activity and malondialdehyde levels in these animals. Our results cautiously suggest the therapeutic effects of MSC-derived exosomes against CNP-induced prostatitis through their antioxidant and anti-inflammatory activities, which should be further considered in the future.
CONFLICT OF INTEREST
None.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
REFERENCES
- Castro-Manrreza, M. E., & Montesinos, J. J. (2015). Immunoregulation by mesenchymal stem cells: Biological aspects and clinical applications. Journal of Immunology Research, 2015, 394917. https://doi.org/10.1155/2015/394917
- Chuang, Y. C., Yoshimura, N., Wu, M., Huang, C. C., Chiang, P. H., Tyagi, P., & Chancellor, M. B. (2007). Intraprostatic capsaicin injection as a novel model for nonbacterial prostatitis and effects of botulinum toxin A. European Urology, 51(4), 1119–1127. https://doi.org/10.1016/j.eururo.2006.11.037
- Ezquer, F., Ezquer, M., Contador, D., Ricca, M., Simon, V., & Conget, P. (2012). The antidiabetic effect of mesenchymal stem cells is unrelated to their transdifferentiation potential but to their capability to restore Th1/Th2 balance and to modify the pancreatic microenvironment. Stem Cells, 30(8), 1664–1674. https://doi.org/10.1002/stem.1132
- Farini, A., Sitzia, C., Erratico, S., Meregalli, M., & Torrente, Y. (2014). Clinical applications of mesenchymal stem cells in chronic diseases. Stem Cells International, 2014, 306573. https://doi.org/10.1155/2014/306573
- Gloire, G., Legrand-Poels, S., & Piette, J. (2006). NF-kappaB activation by reactive oxygen species: Fifteen years later. Biochemical Pharmacology, 72(11), 1493–1505. https://doi.org/10.1016/j.bcp.2006.04.011
- Gyorgy, B., Hung, M. E., Breakefield, X. O., & Leonard, J. N. (2015). Therapeutic applications of extracellular vesicles: Clinical promise and open questions. Annual Review of Pharmacology and Toxicology, 55, 439–464. https://doi.org/10.1146/annurev-pharmtox-010814-124630
- He, X., Dong, Z., Cao, Y., Wang, H., Liu, S., Liao, L., Jin, Y., Yuan, L., & Li, B. (2019). MSC-derived exosome promotes M2 polarization and enhances cutaneous wound healing. Stem Cells International, 2019, 7132708. https://doi.org/10.1155/2019/7132708
- Ishigooka, M., Zermann, D. H., Doggweiler, R., & Schmidt, R. A. (2000). Similarity of distributions of spinal c-Fos and plasma extravasation after acute chemical irritation of the bladder and the prostate. Journal of Urology, 164(5), 1751–1756.
- Karimi, J., Mohammadalipour, A., Sheikh, N., Khodadadi, I., Hashemnia, M., Goudarzi, F., Khanjarsim, V., Solgi, G., Hajilooi, M., Bahabadi, M., Kheiripour, N., & Hedayatyanfard, K. (2020). Protective effects of combined Losartan and Nilotinib on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Drug and Chemical Toxicology, 43(5), 468–478.
- Krieger, J. N., Nyberg, L., Jr., & Nickel, J. C. (1999). NIH consensus definition and classification of prostatitis. Journal of the American Medical Association, 282(3), 236–237. https://doi.org/10.1001/jama.282.3.236
- Lei, Y., Ren, X., Chen, J., Liu, D., & Ruan, J. (2014). Protective effects of grape seed-derived procyanidin extract against carrageenan-induced abacterial prostatitis in rats. Journal of Functional Foods, 7, 416-424. https://doi.org/10.1016/j.jff.2014.01.016
- Li, L., Wang, R., Jia, Y., Rong, R., Xu, M., & Zhu, T. (2019). Exosomes derived from mesenchymal stem cells ameliorate renal ischemic-reperfusion injury through inhibiting inflammation and cell apoptosis. Frontiers in Medicine, 6, 269. https://doi.org/10.3389/fmed.2019.00269
- Lin, L., Zhu, B. P., & Cai, L. (2017). Therapeutic effect of melittin on a rat model of chronic prostatitis induced by Complete Freund's Adjuvant. Biomedicine & Pharmacotherapy, 90, 921–927. https://doi.org/10.1016/j.biopha.2017.04.055
- Lingappan, K. (2018). NF-kappaB in oxidative stress. Current Opinion in Toxicology, 7, 81–86. https://doi.org/10.1016/j.cotox.2017.11.002
- Liu, H., Li, R., Liu, T., Yang, L., Yin, G., & Xie, Q. (2020). Immunomodulatory effects of mesenchymal stem cells and mesenchymal stem cell-derived extracellular vesicles in rheumatoid arthritis. Frontiers in Immunology, 11, 1912–1912. https://doi.org/10.3389/fimmu.2020.01912
- Liu, T., Zhang, L., Joo, D., & Sun, S.-C. (2017). NF-κB signaling in inflammation. Signal Transduction and Targeted Therapy, 2(1), 17023. https://doi.org/10.1038/sigtrans.2017.23
- Liu, X. B., Yang, B. X., Zhang, L., Lu, Y. Z., Gong, M. H., & Tian, J. K. (2015). An in vivo and in vitro assessment of the anti-inflammatory, antinociceptive, and immunomodulatory activities of Clematis terniflora DC. extract, participation of aurantiamide acetate. Journal of Ethnopharmacology, 169, 287–294. https://doi.org/10.1016/j.jep.2015.04.009
- Lou, G., Song, X., Yang, F., Wu, S., Wang, J., Chen, Z., & Liu, Y. (2015). Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. Journal of Hematology & Oncology, 8, 122. https://doi.org/10.1186/s13045-015-0220-7
- Magistro, G., Wagenlehner, F. M., Grabe, M., Weidner, W., Stief, C. G., & Nickel, J. C. (2016). Contemporary management of chronic prostatitis/chronic pelvic pain syndrome. European Urology, 69(2), 286–297. https://doi.org/10.1016/j.eururo.2015.08.061
- Mendt, M., Rezvani, K., & Shpall, E. (2019). Mesenchymal stem cell-derived exosomes for clinical use. Bone Marrow Transplantation, 54(Suppl 2), 789–792. https://doi.org/10.1038/s41409-019-0616-z
- Meng, L.-Q., Yang, F.-Y., Wang, M.-S., Shi, B.-K., Chen, D.-X., Chen, D., Zhou, Q., He, Q.-B., Ma, L.-X., Cheng, W.-L., & Xing, N.-Z. (2018). Quercetin protects against chronic prostatitis in rat model through NF-κB and MAPK signaling pathways. Prostate, 78(11), 790–800. https://doi.org/10.1002/pros.23536
- Ni, H., Yang, S., Siaw-Debrah, F., Hu, J., Wu, K., He, Z., Yang, J., Pan, S., Lin, X., Ye, H., Xu, Z., Wang, F., Jin, K., Zhuge, Q., & Huang, L. (2019). Exosomes derived from bone mesenchymal stem cells ameliorate early inflammatory responses following traumatic brain injury. Frontiers in Neuroscience, 13, 14. https://doi.org/10.3389/fnins.2019.00014
- Nickel, J. C. (2008). Treatment of chronic prostatitis/chronic pelvic pain syndrome. International Journal of Antimicrobial Agents, 31(Suppl 1), S112–S116. https://doi.org/10.1016/j.ijantimicag.2007.07.028
- Oka, M., Ueda, M., Oyama, T., Kyotani, J., & Tanaka, M. (2009). Effect of the phytotherapeutic agent Eviprostat on 17beta-estradiol-induced nonbacterial inflammation in the rat prostate. Prostate, 69(13), 1404–1410. https://doi.org/10.1002/pros.20985
- Phinney, D. G., & Pittenger, M. F. (2017). Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells, 35(4), 851–858. https://doi.org/10.1002/stem.2575
- Pontari, M. A. (2008). Chronic prostatitis/chronic pelvic pain syndrome. Urologic Clinics of North America, 35(1), 81–89. https://doi.org/10.1016/j.ucl.2007.09.005
- Pontari, M. A., & Ruggieri, M. R. (2004). Mechanisms in prostatitis/chronic pelvic pain syndrome. Journal of Urology, 172(3), 839–845. https://doi.org/10.1097/01.ju.0000136002.76898.04
- Raposo, G., & Stoorvogel, W. (2013). Extracellular vesicles: Exosomes, microvesicles, and friends. The Journal of Cell Biology, 200(4), 373–383. https://doi.org/10.1083/jcb.201211138
- Rider, M. A., Hurwitz, S. N., & Meckes, D. G. (2016). ExtraPEG: A polyethylene glycol-based method for enrichment of extracellular vesicles. Scientific Reports, 6(1), 23978. https://doi.org/10.1038/srep23978
- Rong, X., Liu, J., Yao, X., Jiang, T., Wang, Y., & Xie, F. (2019). Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt/beta-catenin pathway. Stem Cell Research & Therapy, 10(1), 98. https://doi.org/10.1186/s13287-019-1204-2
- Rosa-Fernandes, L., Rocha, V. B., Carregari, V. C., Urbani, A., & Palmisano, G. (2017). A perspective on extracellular vesicles proteomics. Frontiers in chemistry, 5, 102–102. https://doi.org/10.3389/fchem.2017.00102
- Ti, D., Hao, H., Tong, C., Liu, J., Dong, L., Zheng, J., Zhao, Y., Liu, H., Fu, X., & Han, W. (2015). LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b. Journal of Translational Medicine, 13(1), 308. https://doi.org/10.1186/s12967-015-0642-6
- Wang, L., Pei, S., Han, L., Guo, B., Li, Y., Duan, R., Yao, Y., Xue, B., Chen, X., & Jia, Y. (2018). Mesenchymal stem cell-derived exosomes reduce A1 astrocytes via downregulation of phosphorylated NFkappaB P65 subunit in spinal cord injury. Cellular Physiology and Biochemistry, 50(4), 1535–1559. https://doi.org/10.1159/000494652
- Wen, D., Peng, Y., Liu, D., Weizmann, Y., & Mahato, R. I. (2016). Mesenchymal stem cell and derived exosome as small RNA carrier and Immunomodulator to improve islet transplantation. Journal of Controlled Release, 238, 166–175. https://doi.org/10.1016/j.jconrel.2016.07.044
- Willis, G. R., Fernandez-Gonzalez, A., Anastas, J., Vitali, S. H., Liu, X., Ericsson, M., Kwong, A., Mitsialis, S. A., & Kourembanas, S. (2018). Mesenchymal stromal cell exosomes ameliorate experimental bronchopulmonary dysplasia and restore lung function through macrophage immunomodulation. American Journal of Respiratory and Critical Care Medicine, 197(1), 104–116. https://doi.org/10.1164/rccm.201705-0925OC
- Yanez-Mo, M., Siljander, P. R., Andreu, Z., Zavec, A. B., Borras, F. E., Buzas, E. I., Buzas, K., Casal, E., Cappello, F., Carvalho, J., Colas, E., Cordeiro-da Silva, A., Fais, S., Falcon-Perez, J. M., Ghobrial, I. M., Giebel, B., Gimona, M., Graner, M., Gursel, I., … De Wever, O. (2015). Biological properties of extracellular vesicles and their physiological functions. Journal of Extracellular Vesicles, 4, 27066. https://doi.org/10.3402/jev.v4.27066
- Yang, X., Yuan, L., Chen, J., Xiong, C., & Ruan, J. (2014). Multitargeted protective effect of Abacopteris penangiana against carrageenan-induced chronic prostatitis in rats. Journal of Ethnopharmacology, 151(1), 343–351. https://doi.org/10.1016/j.jep.2013.10.061
- Zaidi, N., Thomas, D., & Chughtai, B. (2018). Management of chronic prostatitis (CP). Current Urology Reports, 19(11), 88. https://doi.org/10.1007/s11934-018-0841-9
- Zhang, Y., Liu, Y., Liu, H., & Tang, W. H. (2019). Exosomes: Biogenesis, biologic function and clinical potential. Cell & Bioscience, 9(1), 19. https://doi.org/10.1186/s13578-019-0282-2
