Abstract
Introduction and hypothesis
We investigated the effects of bladder wall injection of mesenchymal stem cells (MSCs) on bladder tissues, function, and nociceptive behavior in a chemically induced interstitial cystitis-like rat model.
Methods
Chemical cystitis of female rats was induced by intravesical instillation of 0.1 N hydrochloride (HCl) once a week for 2 weeks. Bladders were harvested 1, 2, 3, and 4 weeks after the second application for histological examination. Adipose-derived MSCs (HCl + MSCs) or phosphate-buffered saline (HCl + PBS) was injected into the bladder wall at the time of the second application of HCl. Histological examination, nociceptive behavior, and cystometrograms were evaluated 2 weeks after the injection compared with controls, which received instillation and injection of PBS into the bladder (sham + PBS).
Results
The number of mast cells and expression of tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β) were significantly increased at 1 and 2 weeks, and expression of collagen fibers was significantly increased from 2–4 weeks after the second application of HCl. Significantly increased nociceptive behavior, number of mast cells, expression of TNF-α, TGF-β, and collagen fibers were observed in HCl + PBS compared with sham + PBS, whereas these changes were significantly decreased in HCl + MSCs compared with HCl + PBS. In addition, bladder capacity and voiding threshold pressures were significantly decreased in HCl + PBS but not in HCl + MSCs compared with sham + PBS.
Conclusions
The results suggest that bladder injection of MSCs ameliorates inflammation and fibrosis in bladder tissues, bladder overactivity, and nociception in a rat model of chemically induced cystitis.
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Abbreviations
- HCl:
-
Hydrochloride
- IC:
-
Interstitial cystitis
- MSCs:
-
Mesenchymal stem cells
- PBS:
-
Phosphate buffered saline
- TNF-α:
-
Tumor necrosis factor-α
- TGF-β:
-
Transforming growth factor-β
- VEGF:
-
Vascular endothelial growth factor
References
Homma Y, Ueda T, Tomoe H, Lin AT, Kuo HC, et al. Clinical guidelines for interstitial cystitis and hypersensitive bladder updated in 2015. Int J Urol. 2016;23:542–9.
van de Merwe JP, Nordling J, Bouchelouche P, Bouchelouche K, Cervigni M, et al. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal. Eur Urol. 2008;53:60–7.
Richter B, Hesse U, Hansen AB, Horn T, Mortensen SO, et al. Bladder pain syndrome/interstitial cystitis in a Danish population: a study using the 2008 criteria of the European Society for the Study of interstitial cystitis. BJU Int. 2010;105:660–7.
Maggi CA, Lecci A, Santicioli P, Del Bianco E, Giuliani S. Cyclophosphamide cystitis in rats: involvement of capsaicin-sensitive primary afferents. J Auton Nerv Syst. 1992;38:201–8.
Kim A, Yu HY, Heo J, Song M, Shin JH, et al. Mesenchymal stem cells protect against the tissue fibrosis of ketamine-induced cystitis in rat bladder. Sci Rep. 2016;6:30881.
McMahon SB, Abel C. A model for the study of visceral pain states: chronic inflammation of the chronic decerebrate rat urinary bladder by irritant chemicals. Pain. 1987;28:109–27.
Shimizu I, Kawashima K, Hosoki K. Urodynamics in acetone-induced cystitis of anesthetized rats. Neurourol Urodyn. 1999;18:115–27.
Soler R, Bruschini H, Truzzi JC, Martins JR, Camara NO, et al. Urinary glycosaminoglycans excretion and the effect of dimethyl sulfoxide in an experimental model of non-bacterial cystitis. Int Braz J Urol. 2008;34:503–11. discussion 11
Rivas DA, Chancellor MB, Shupp-Byrne S, Shenot PJ, McHugh K, et al. Molecular marker for development of interstitial cystitis in rat model: isoactin gene expression. J Urol. 1997;157:1937–40.
Westropp JL, Buffington CA. In vivo models of interstitial cystitis. J Urol. 2002;167:694–702.
Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells. 2007;25:2739–49.
Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood. 2007;110:3499–506.
Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood. 2005;105:2821–7.
Jiang XX, Zhang Y, Liu B, Zhang SX, Wu Y, et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood. 2005;105:4120–6.
Beyth S, Borovsky Z, Mevorach D, Liebergall M, Gazit Z, et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood. 2005;105:2214–9.
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–7.
Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E, Stornaiuolo A, et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Science. 1998;279:1528–30.
Dezawa M, Ishikawa H, Itokazu Y, Yoshihara T, Hoshino M, et al. Bone marrow stromal cells generate muscle cells and repair muscle degeneration. Science. 2005;309:314–7.
Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7:211–28.
Yanez R, Lamana ML, Garcia-Castro J, Colmenero I, Ramirez M, et al. Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells. 2006;24:2582–91.
Puissant B, Barreau C, Bourin P, Clavel C, Corre J, et al. Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol. 2005;129:118–29.
Song M, Lim J, Yu HY, Park J, Chun JY, et al. Mesenchymal stem cell therapy alleviates interstitial cystitis by activating Wnt signaling pathway. Stem Cells Dev. 2015;24:1648–57.
Watanabe T, Maruyama S, Yamamoto T, Kamo I, Yasuda K, et al. Increased urethral resistance by periurethral injection of low serum cultured adipose-derived mesenchymal stromal cells in rats. Int J Urol. 2011;18:659–66.
Nishiguchi J, Sasaki K, Seki S, Chancellor MB, Erickson KA, et al. Effects of isolectin B4-conjugated saporin, a targeting cytotoxin, on bladder overactivity induced by bladder irritation. Eur J Neurosci. 2004;20:474–82.
Saitoh C, Yokoyama H, Chancellor MB, de Groat WC, Yoshimura N. Comparison of voiding function and nociceptive behavior in two rat models of cystitis induced by cyclophosphamide or acetone. Neurourol Urodyn. 2010;29:501–5.
Furuta A, Suzuki Y, Kimura S, Koike Y, Egawa S, et al. Combination therapy with beta3 -adrenoceptor agonists and muscarinic acetylcholine receptor antagonists: efficacy in rats with bladder overactivity. Int J Urol. 2016;23:425–30.
Hirose Y, Yamamoto T, Nakashima M, Funahashi Y, Matsukawa Y, et al. Injection of dental pulp stem cells promotes healing of damaged bladder tissue in a rat model of chemically induced cystitis. Cell Transplant. 2016;25:425–36.
Acknowledgements
This study was supported by JSPS KAKENHI Grant Number 15K10633.
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Furuta, A., Yamamoto, T., Igarashi, T. et al. Bladder wall injection of mesenchymal stem cells ameliorates bladder inflammation, overactivity, and nociception in a chemically induced interstitial cystitis-like rat model. Int Urogynecol J 29, 1615–1622 (2018). https://doi.org/10.1007/s00192-018-3592-8
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DOI: https://doi.org/10.1007/s00192-018-3592-8