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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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New therapeutic approach with extracellular vesicles from stem cells for interstitial cystitis/bladder pain syndrome

  • Dayem, Ahmed Abdal (Department of Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University) ;
  • Song, Kwonwoo (Department of Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University) ;
  • Lee, Soobin (Department of Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University) ;
  • Kim, Aram (Department of Urology, Konkuk University Medical Center, Konkuk University School of Medicine) ;
  • Cho, Ssang-Goo (Department of Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University)
  • Received : 2022.02.10
  • Accepted : 2022.03.28
  • Published : 2022.05.31
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Abstract

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating chronic disorder characterized by suprapubic pain and urinary symptoms such as urgency, nocturia, and frequency. The prevalence of IC/BPS is increasing as diagnostic criteria become more comprehensive. Conventional pharmacotherapy against IC/BPS has shown suboptimal effects, and consequently, patients with end-stage IC/BPS are subjected to surgery. The novel treatment strategies should have two main functions, anti-inflammatory action and the regeneration of glycosaminoglycan and urothelium layers. Stem cell therapy has been shown to have dual functions. Mesenchymal stem cells (MSCs) are a promising therapeutic option for IC/BPS, but they come with several shortcomings, such as immune activation and tumorigenicity. MSC-derived extracellular vesicles (MSC-EVs) hold numerous therapeutic cargos and are thus a viable cell-free therapeutic option. In this review, we provide a brief overview of IC/BPS pathophysiology and limitations of the MSC-based therapies. Then we provide a detailed explanation and discussion of therapeutic applications of EVs in IC/BPS as well as the possible mechanisms. We believe our review will give an insight into the strengths and drawbacks of EV-mediated IC/BPS therapy and will provide a basis for further development.

Keywords

Acknowledgement

This study was supported by a grant from the National Research Foundation (NRF), funded by the Ministry of Education (NRF-2019R1I1A2A01063045) and the Korean Government (Ministry of Education, Science, and Technology) under Grant numbers 2019M3A9H1030682 and 2020R1F1A106709912.

References

  1. McDermott P (2009) Painful bladder syndrome/interstitial cystitis (history, epidemiology, symptoms, diagnosis and treatments). Int J Urol Nurs 3, 16-23 https://doi.org/10.1111/j.1749-771X.2009.01059.x
  2. Suskind AM, Berry SH, Ewing BA, Elliott MN, Suttorp MJ and Clemens JQ (2013) The prevalence and overlap of interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome in men: results of the RAND Interstitial Cystitis Epidemiology male study. J Urol 189, 141-145 https://doi.org/10.1016/j.juro.2012.08.088
  3. Clemens JQ, Clauw DJ, Kreder K et al (2015) Comparison of baseline urological symptoms in men and women in the MAPP research cohort. J Urol 193, 1554-1558 https://doi.org/10.1016/j.juro.2014.11.016
  4. Kim A, Han JY, Ryu CM et al (2017) Histopathological characteristics of interstitial cystitis/bladder pain syndrome without Hunner lesion. Histopathology 71, 415-424 https://doi.org/10.1111/his.13235
  5. Bo K, Frawley HC, Haylen BT et al (2017) An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for the conservative and nonpharmacological management of female pelvic floor dysfunction. Int Urogynecol J 28, 191-213 https://doi.org/10.1007/s00192-016-3123-4
  6. Ogawa T, Ishizuka O, Ueda T, Tyagi P, Chancellor MB and Yoshimura N (2015) Current and emerging drugs for interstitial cystitis/bladder pain syndrome (IC/BPS). Expert Opin Emerg Drugs 20, 555-570 https://doi.org/10.1517/14728214.2015.1105216
  7. Hu P, Meyers S, Liang FX et al (2002) Role of membrane proteins in permeability barrier function: uroplakin ablation elevates urothelial permeability. Am J Physiol Renal Physiol 283, F1200-F1207 https://doi.org/10.1152/ajprenal.00043.2002
  8. Visnjar T, Kocbek P and Kreft ME (2012) Hyperplasia as a mechanism for rapid resealing urothelial injuries and maintaining high transepithelial resistance. Histochem Cell Biol 137, 177-186 https://doi.org/10.1007/s00418-011-0893-0
  9. Sun TT, Zhao H, Provet J, Aebi U and Wu XR (1996) Formation of asymmetric unit membrane during urothelial differentiation. Mol Biol Rep 23, 3-11 https://doi.org/10.1007/BF00357068
  10. Wu XR, Kong XP, Pellicer A, Kreibich G and Sun TT (2009) Uroplakins in urothelial biology, function, and disease. Kidney Int 75, 1153-1165 https://doi.org/10.1038/ki.2009.73
  11. Osborn SL, Thangappan R, Luria A, Lee JH, Nolta J and Kurzrock EA (2014) Induction of human embryonic and induced pluripotent stem cells into urothelium. Stem Cells Transl Med 3, 610-619 https://doi.org/10.5966/sctm.2013-0131
  12. Colopy SA, Bjorling DE, Mulligan WA and Bushman W (2014) A population of progenitor cells in the basal and intermediate layers of the murine bladder urothelium contributes to urothelial development and regeneration. Dev Dyn 243, 988-998 https://doi.org/10.1002/dvdy.24143
  13. Wang C, Ross WT and Mysorekar IU (2017) Urothelial generation and regeneration in development, injury, and cancer. Dev Dyn 246, 336-343 https://doi.org/10.1002/dvdy.24487
  14. Petrovic V, Stankovic J and Stefanovic V (2011) Tissue engineering of the urinary bladder: current concepts and future perspectives. TheScientificWorldJOURNAL 11, 1479-1488 https://doi.org/10.1100/tsw.2011.138
  15. Hautmann RE (2003) Urinary diversion: ileal conduit to neobladder. Urol 169, 834-842 https://doi.org/10.1097/01.ju.0000029010.97686.eb
  16. Abdal Dayem A, Kim K, Lee SB, Kim A and Cho SG (2020) Application of adult and pluripotent stem cells in interstitial cystitis/bladder pain syndrome therapy: methods and perspectives. J Clin Med 9, 766 https://doi.org/10.3390/jcm9030766
  17. Hanno PM, Erickson D, Moldwin R and Faraday MM (2015) Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. Urol 193, 1545-1553 https://doi.org/10.1016/j.juro.2015.01.086
  18. Shin JH, Ryu CM, Yu HY, Shin DM and Choo MS (2020) Current and future directions of stem cell therapy for bladder dysfunction. Stem Cell Rev Rep 16, 82-93 https://doi.org/10.1007/s12015-019-09922-2
  19. Tabata H, Sasaki M, Kataoka-Sasaki Y et al (2021) Possible role of intravenous administration of mesenchymal stem cells to alleviate interstitial cystitis/bladder pain syndrome in a Toll-like receptor-7 agonist-induced experimental animal model in rat. BMC Urol 21, 156 https://doi.org/10.1186/s12894-021-00923-3
  20. Bateman ME, Strong AL, Gimble JM and Bunnell BA (2018) Concise review: using fat to fight disease: a systematic review of nonhomologous adipose-derived stromal/stem cell therapies. Stem Cells 36, 1311-1328 https://doi.org/10.1002/stem.2847
  21. Borakati A, Mafi R, Mafi P and Khan WS (2018) A systematic review and meta-analysis of clinical trials of mesenchymal stem cell therapy for cartilage repair. Curr Stem Cell Res Ther 13, 215-225 https://doi.org/10.2174/1574888X12666170915120620
  22. Yim H, Jeong H, Cho Y, Jeong S and Oh I (2016) Safety of mesenchymal stem cell therapy: a systematic review and meta-analysis. Cytotherapy 18, S132
  23. Lener T, Gimona M, Aigner L et al (2015) Applying extracellular vesicles based therapeutics in clinical trials-an ISEV position paper. J Extracell Vesicles 4, 30087 https://doi.org/10.3402/jev.v4.30087
  24. Witwer KW, Van Balkom BW, Bruno S et al (2019) Defining mesenchymal stromal cell (MSC)-derived small extracellular vesicles for therapeutic applications. J Extracell Vesicles 8, 1609206 https://doi.org/10.1080/20013078.2019.1609206
  25. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S and Wood MJ (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29, 341-345 https://doi.org/10.1038/nbt.1807
  26. Cloutier N, Pare A, Farndale RW et al (2012) Platelets can enhance vascular permeability. Blood 120, 1334-1343 https://doi.org/10.1182/blood-2012-02-413047
  27. Wahlgren J, Karlson TDL, Brisslert M et al (2012) Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes. Nucleic Acids Res 40, e130 https://doi.org/10.1093/nar/gks463
  28. Ohno S-i, Takanashi M, Sudo K et al (2013) Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol Ther 21, 185-191 https://doi.org/10.1038/mt.2012.180
  29. Akao Y, Iio A, Itoh T et al (2011) Microvesicle-mediated RNA molecule delivery system using monocytes/macrophages. Mol Ther 19, 395-399 https://doi.org/10.1038/mt.2010.254
  30. Thery C, Ostrowski M and Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9, 581-593 https://doi.org/10.1038/nri2567
  31. Buzas EI, Gyorgy B, Nagy G, Falus A and Gay S (2014) Emerging role of extracellular vesicles in inflammatory diseases. Nat Rev Rheumatol 10, 356-364 https://doi.org/10.1038/nrrheum.2014.19
  32. Borger V, Bremer M, Ferrer-Tur R et al (2017) Mesenchymal stem/stromal cell-derived extracellular vesicles and their potential as novel immunomodulatory therapeutic agents. Int J Mol Sci 18, 1450 https://doi.org/10.3390/ijms18071450
  33. McLennan MT (2014) Interstitial cystitis: epidemiology, pathophysiology, and clinical presentation. Obstet Gynecol Clin 41, 385-395 https://doi.org/10.1016/j.ogc.2014.05.004
  34. Kim H-J (2016) Update on the pathology and diagnosis of interstitial cystitis/bladder pain syndrome: a review. Int Neurourol J 20, 13 https://doi.org/10.5213/inj.1632522.261
  35. Yoshimura N, Oguchi T, Yokoyama H et al (2014) Bladder afferent hyperexcitability in bladder pain syndrome/interstitial cystitis. Int J Urol 21, 18-25 https://doi.org/10.1111/iju.12308
  36. Lewis SA (2000) Everything you wanted to know about the bladder epithelium but were afraid to ask. Am J Physiol Renal Physiol 278, F867-F874 https://doi.org/10.1152/ajprenal.2000.278.6.f867
  37. Neuhaus J, Heinrich M, Schlichting N et al (2007) Structure and function of suburothelial myofibroblasts in the human urinary bladder under normal and pathological conditions. Der Urologe Ausg A 46, 1197-1202 https://doi.org/10.1007/s00120-007-1480-9
  38. Parsons CL (2011) The role of a leaky epithelium and potassium in the generation of bladder symptoms in interstitial cystitis/overactive bladder, urethral syndrome, prostatitis and gynaecological chronic pelvic pain. BJU Int 107, 370-375 https://doi.org/10.1111/j.1464-410X.2010.09843.x
  39. Birder L and Andersson K-E (2013) Urothelial signaling. Physiol Rev 93, 653-680 https://doi.org/10.1152/physrev.00030.2012
  40. Lopez SR and Mangir N (2021) Current standard of care in treatment of bladder pain syndrome/interstitial cystitis. Ther Adv Urol 13, 17562872211022478
  41. Warren JW, Brown V, Jacobs S, Horne L, Langenberg P and Greenberg P (2008) Urinary tract infection and inflammation at onset of interstitial cystitis/painful bladder syndrome. Urology 71, 1085-1090 https://doi.org/10.1016/j.urology.2007.12.091
  42. Shea-Donohue T, Stiltz J, Zhao A and Notari L (2010) Mast cells. Curr Gastroenterol Rep 12, 349-357 https://doi.org/10.1007/s11894-010-0132-1
  43. Gamper M, Regauer S, Welter J, Eberhard J and Viereck V (2015) Are mast cells still good biomarkers for bladder pain syndrome/interstitial cystitis? Urol 193, 1994-2000 https://doi.org/10.1016/j.juro.2015.01.036
  44. Van De Merwe JP (2007) Interstitial cystitis and systemic autoimmune diseases. Nat Clin Pract Urol 4, 484-491 https://doi.org/10.1038/ncpuro0874
  45. Lee C-K, Tsai CP, Liao TL et al (2019) Overactive bladder and bladder pain syndrome/interstitial cystitis in primary Sjogren's syndrome patients: a nationwide population-based study. PLoS One 14, e0225455 https://doi.org/10.1371/journal.pone.0225455
  46. Phinney DG and Pittenger MF (2017) Concise review: msc-derived exosomes for cell-free therapy. Stem Cells 35, 851-858 https://doi.org/10.1002/stem.2575
  47. Wu S, Cheng Z, Liu G et al (2013) Urothelial differentiation of human umbilical cord-derived mesenchymal stromal cells in vitro. Anal Cell Pathol 36, 63-69 https://doi.org/10.1155/2013/274640
  48. Song B, Jiang W, Alraies A et al (2016) Bladder smooth muscle cells differentiation from dental pulp stem cells: future potential for bladder tissue engineering. Stem Cells Int 2016, 6979368 https://doi.org/10.1155/2016/6979368
  49. Jiang W, Wang D, Alraies A et al (2019) Wnt-GSK3β/β-catenin regulates the differentiation of dental pulp stem cells into bladder smooth muscle cells. Stem cells international 2019
  50. Kim A, Shin DM and Choo MS (2016) Stem cell therapy for interstitial cystitis/bladder pain syndrome. Curr Urol Rep 17, 1-9 https://doi.org/10.1007/s11934-015-0563-1
  51. Kuriyan AE, Albini TA, Townsend JH et al (2017) Vision loss after intravitreal injection of autologous "stem cells" for AMD. N Engl J Med 376, 1047-1053 https://doi.org/10.1056/NEJMoa1609583
  52. Barkholt L, Flory E, Jekerle V et al (2013) Risk of tumorigenicity in mesenchymal stromal cell-based therapies-bridging scientific observations and regulatory viewpoints. Cytotherapy 15, 753-759 https://doi.org/10.1016/j.jcyt.2013.03.005
  53. Herberts CA, Kwa MS and Hermsen HP (2011) Risk factors in the development of stem cell therapy. J Transl Med 9, 1-14 https://doi.org/10.1186/1479-5876-9-1
  54. Musial-Wysocka A, Kot M and Majka M (2019) The pros and cons of mesenchymal stem cell-based therapies. Cell Transplant 28, 801-812 https://doi.org/10.1177/0963689719837897
  55. Kraitchman DL, Tatsumi M, Gilson WD et al (2005) Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction. Circulation 112, 1451-1461 https://doi.org/10.1161/CIRCULATIONAHA.105.537480
  56. McBride C, Gaupp D and Phinney D (2003) Quantifying levels of transplanted murine and human mesenchymal stem cells in vivo by realtime PCR. Cytotherapy 5, 7-18 https://doi.org/10.1080/14653240310000038
  57. Francois S, Bensidhoum M, Mouiseddine M et al (2006) Local irradiation not only induces homing of human mesenchymal stem cells at exposed sites but promotes their widespread engraftment to multiple organs: a study of their quantitative distribution after irradiation damage. Stem cells 24, 1020-1029 https://doi.org/10.1634/stemcells.2005-0260
  58. Toma C, Wagner WR, Bowry S, Schwartz A and Villanueva F (2009) Fate of culture-expanded mesenchymal stem cells in the microvasculature: in vivo observations of cell kinetics. Circ Res 104, 398-402 https://doi.org/10.1161/CIRCRESAHA.108.187724
  59. Wei W, Ao Q, Wang X et al (2021) Mesenchymal stem cell-derived exosomes: a promising biological tool in nanomedicine. Front Pharmacol 11, 590470 https://doi.org/10.3389/fphar.2020.590470
  60. Kuret T, Peskar D, Erman A and Veranic P (2021) A systematic review of therapeutic approaches used in experimental models of interstitial cystitis/bladder pain syndrome. Biomedicines 9, 865 https://doi.org/10.3390/biomedicines9080865
  61. da Silva Meirelles L, Caplan AI and Nardi NB (2008) In search of the in vivo identity of mesenchymal stem cells. Stem cells 26, 2287-2299 https://doi.org/10.1634/stemcells.2007-1122
  62. Caplan AI and Correa D (2011) The MSC: an injury drugstore. Cell Stem Cell 9, 11-15 https://doi.org/10.1016/j.stem.2011.06.008
  63. Gnecchi M, He H, Liang OD et al (2005) Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med 11, 367-368 https://doi.org/10.1038/nm0405-367
  64. Goolaerts A, Pellan-Randrianarison N, Larghero J et al (2014) Conditioned media from mesenchymal stromal cells restore sodium transport and preserve epithelial permeability in an in vitro model of acute alveolar injury. Am J Physiol - Lung Cell Mol Physiol 306, L975-L985 https://doi.org/10.1152/ajplung.00242.2013
  65. Tremain N, Korkko J, Ibberson D, Kopen GC, DiGirolamo C and Phinney DG (2001) MicroSAGE analysis of 2,353 expressed genes in a single cell-derived colony of undifferentiated human mesenchymal stem cells reveals mRNAs of multiple cell lineages. Stem Cells 19, 408-418 https://doi.org/10.1634/stemcells.19-5-408
  66. Ren J, Jin P, Sabatino M et al (2011) Global transcriptome analysis of human bone marrow stromal cells (BMSC) reveals proliferative, mobile and interactive cells that produce abundant extracellular matrix proteins, some of which may affect BMSC potency. Cytotherapy 13, 661-674 https://doi.org/10.3109/14653249.2010.548379
  67. Tian H, Bharadwaj S, Liu Y et al (2010) Myogenic differentiation of human bone marrow mesenchymal stem cells on a 3D nano fibrous scaffold for bladder tissue engineering. Biomaterials 31, 870-877 https://doi.org/10.1016/j.biomaterials.2009.10.001
  68. Sharma AK, Hota PV, Matoka DJ et al (2010) Urinary bladder smooth muscle regeneration utilizing bone marrow derived mesenchymal stem cell seeded elastomeric poly (1, 8-octanediol-co-citrate) based thin films. Biomaterials 31, 6207-6217 https://doi.org/10.1016/j.biomaterials.2010.04.054
  69. Zhang Y, Lin HK, Frimberger D, Epstein RB and Kropp BP (2005) Growth of bone marrow stromal cells on small intestinal submucosa: an alternative cell source for tissue engineered bladder. BJU Int 96, 1120-1125 https://doi.org/10.1111/j.1464-410X.2005.05741.x
  70. Ohishi M and Schipani E (2010) Bone marrow mesenchymal stem cells. J Cell Biochem 109, 277-282 https://doi.org/10.1002/jcb.22399
  71. Yu B, Kim HW, Gong M et al (2015) Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int J Cardiol 182, 349-360 https://doi.org/10.1016/j.ijcard.2014.12.043
  72. Mendt M, Rezvani K and Shpall E (2019) Mesenchymal stem cell-derived exosomes for clinical use. Bone Marrow Transplant 54, 789-792 https://doi.org/10.1038/s41409-019-0616-z
  73. Wen C, Xie L and Hu C (2022) Roles of mesenchymal stem cells and exosomes in interstitial cystitis/bladder pain syndrome. J Cell Mol Med 26, 624-635 https://doi.org/10.1111/jcmm.17132
  74. Parekkadan B and Milwid JM (2010) Mesenchymal stem cells as therapeutics. Annu Rev Biomed Eng 12, 87-117 https://doi.org/10.1146/annurev-bioeng-070909-105309
  75. Kang H, Kim J and Park J (2017) Methods to isolate extracellular vesicles for diagnosis. Micro Nano Syst Lett 5, 15 https://doi.org/10.1186/s40486-017-0049-7
  76. Zhao Z, Wijerathne H, Godwin AK and Soper SA (2021) Isolation and analysis methods of extracellular vesicles (EVs). Extracell Vesicles Circ Nucl Acids 2, 80-103
  77. Thery C, Witwer KW, Aikawa E et al (2018) Minimal information for studies of extracellular vesicles 2018 (MISEV 2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 7, 1535750 https://doi.org/10.1080/20013078.2018.1535750
  78. Ludwig N, Whiteside TL and Reichert TE (2019) Challenges in exosome isolation and analysis in health and disease. Int J Mol Sci 20, 4684 https://doi.org/10.3390/ijms20194684
  79. Harding C, Heuser J and Stahl P (1983) Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol 97, 329-339 https://doi.org/10.1083/jcb.97.2.329
  80. Cocucci E and Meldolesi J (2015) Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends Cell Biol 25, 364-372 https://doi.org/10.1016/j.tcb.2015.01.004
  81. Lai RC, Yeo RW and Lim SK (2015) Mesenchymal stem cell exosomes. Semin Cell Dev Biol 40, 82-88 https://doi.org/10.1016/j.semcdb.2015.03.001
  82. Giebel B, Kordelas L and Borger V (2017) Clinical potential of mesenchymal stem/stromal cell-derived extracellular vesicles. Stem Cell Investig 4, 84 https://doi.org/10.21037/sci.2017.09.06
  83. Yeo RWY and Lim SK (2016) Exosomes and their therapeutic applications. ADVANCES IN PHARMACEUTICAL CELL THERAPY: Principles of Cell-Based Biopharmaceuticals 477-501
  84. Toh WS, Lai RC, Hui JHP and Lim SK (2017) MSC exosome as a cell-free MSC therapy for cartilage regeneration: implications for osteoarthritis treatment. Semin Cell Dev Biol 67, 56-64 https://doi.org/10.1016/j.semcdb.2016.11.008
  85. Zhang S, Chuah SJ, Lai RC, Hui JHP, Lim SK and Toh WS (2018) MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials 156, 16-27 https://doi.org/10.1016/j.biomaterials.2017.11.028
  86. Hu S, Wang X, Li Z et al (2021) Platelet membrane and stem cell exosome hybrids enhance cellular uptake and targeting to heart injury. Nano Today 39, 101210 https://doi.org/10.1016/j.nantod.2021.101210
  87. Popowski KD, Dinh PUC, George A, Lutz H and Cheng K (2021) Exosome therapeutics for COVID-19 and respiratory viruses. View (Beijing) 2, 20200186
  88. Gonzalez-King H, Garcia NA, Ontoria-Oviedo I, Ciria M, Montero JA and Sepulveda P (2017) Hypoxia inducible factor-1α potentiates jagged 1-mediated angiogenesis by mesenchymal stem cell-derived exosomes. Stem Cells 35, 1747-1759 https://doi.org/10.1002/stem.2618
  89. Anderson JD, Johansson HJ, Graham CS et al (2016) Comprehensive proteomic analysis of mesenchymal stem cell exosomes reveals modulation of angiogenesis via nuclear factor-kappaB signaling. Stem Cells 34, 601-613 https://doi.org/10.1002/stem.2298
  90. Adamowicz J, Pokrywczynska M and Drewa T (2014) Conditioned medium derived from mesenchymal stem cells culture as a intravesical therapy for cystitis interstitials. Med Hypotheses 82, 670-673 https://doi.org/10.1016/j.mehy.2014.02.027
  91. Xie J, Liu B, Chen J et al (2018) Umbilical cord-derived mesenchymal stem cells alleviated inflammation and inhibited apoptosis in interstitial cystitis via AKT/mTOR signaling pathway. Biochem Biophys Res Commun 495, 546-552 https://doi.org/10.1016/j.bbrc.2017.11.072
  92. Wiafe B, Adesida A, Churchill T, Adewuyi EE, Li Z and Metcalfe P (2017) Hypoxia-increased expression of genes involved in inflammation, dedifferentiation, pro-fibrosis, and extracellular matrix remodeling of human bladder smooth muscle cells. In Vitro Cell Dev Biol Anim 53, 58-66 https://doi.org/10.1007/s11626-017-0163-0
  93. Wiafe B, Adesida A, Churchill T and Metcalfe P (2018) Mesenchymal stem cells inhibit hypoxia-induced inflammatory and fibrotic pathways in bladder smooth muscle cells. World J Urol 36, 1157-1165 https://doi.org/10.1007/s00345-018-2247-1
  94. Lv JW, Wen W, Jiang C et al (2017) Inhibition of microRNA-214 promotes epithelial-mesenchymal transition process and induces interstitial cystitis in postmenopausal women by upregulating Mfn2. Exp Mol Med 49, e357-e357 https://doi.org/10.1038/emm.2017.98
  95. Wang Y, Zhao R, Liu D et al (2018) Exosomes derived from miR-214-enriched bone marrow-derived mesenchymal stem cells regulate oxidative damage in cardiac stem cells by targeting CaMKII. Oxid Med Cell Longev 2018, 4971261 https://doi.org/10.1155/2018/4971261
  96. Yang C, Lim W, Park J, Park S, You S and Song G (2019) Anti-inflammatory effects of mesenchymal stem cell-derived exosomal microRNA-146a-5p and microRNA-548e-5p on human trophoblast cells. Mol Hum Reprod 25, 755-771 https://doi.org/10.1093/molehr/gaz054
  97. Li Y, Zhang J, Shi J et al (2021) Exosomes derived from human adipose mesenchymal stem cells attenuate hypertrophic scar fibrosis by miR-192-5p/IL-17RA/Smad axis. Stem Cell Res Ther 12, 221 https://doi.org/10.1186/s13287-021-02290-0
  98. Xie L and Zeng Y (2020) Therapeutic potential of exosomes in pulmonary fibrosis. Front pharmacol 11, 590972-590972 https://doi.org/10.3389/fphar.2020.590972
  99. Tavasolian F, Hosseini AZ, Soudi S and Naderi M (2020) miRNA-146a improves immunomodulatory effects of MSC-derived exosomes in rheumatoid arthritis. Curr Gene Ther 20, 297-312 https://doi.org/10.2174/1566523220666200916120708