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Effects of human Muse cells on bladder inflammation, overactivity, and nociception in a chemically induced Hunner-type interstitial cystitis-like rat model

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Abstract

Introduction and hypothesis

We investigated the effects of locally administered human multilineage-differentiating stress enduring (Muse) cells, nontumorigenic pluripotent-like endogenous stem cells, on bladder tissues, function, and nociceptive behavior in a chemically induced Hunner-type interstitial cystitis (HIC)-like rat model without immunosuppressant.

Methods

Chemical cystitis was induced by intravesical instillation of 0.2 N hydrochloride (HCl) for 15 min in female F344 rats. SSEA-3+ Muse cells, SSEA-3− non-Muse cells or Hanks' balanced salt solution (HBSS; vehicle) were injected into the anterior and posterior bladder wall at each 1×104 cells/10 μl 6 h after HCl application. The sham group received HBSS without HCl instillation. Urinary frequency was assessed using metabolic cages, cystometrograms, nociceptive behavior, and histological analysis of the bladder and L6 spinal cord.

Results

Increases in urinary frequency and decreases in bladder capacity compared with the sham group were observed in the vehicle and non-Muse groups, but not in the Muse group, at 1 week. Significant increases in nociceptive behavior compared with the sham group and the expression of TNFα in the bladder and c-Fos in the bilateral dorsal horns of L6 spinal cord were also observed in the vehicle and non-Muse groups, whereas these changes were not seen in the Muse group at 1 week. Histological analysis exhibited a higher proportion of injected Muse cells remaining in the urothelial basal layer and lamina propria of the bladder than non-Muse cells until 4 weeks.

Conclusions

Muse cell therapy could be a promising modality for treating HIC.

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Abbreviations

BC:

Bladder capacity

BM:

Bone marrow

BP:

Baseline pressure

HBSS:

Hanks' balanced salt solution

HCl:

Hydrochloride

HE:

Hematoxylin eosin

HGF:

Hepatocyte growth factor

HIC:

Hunner-type interstitial cystitis

HLA:

Human leucocyte antigen

IC/BPS:

Interstitial cystitis/bladder pain syndrome

MSCs:

Mesenchymal stem cells

Muse:

Multilineage-differentiating stress enduring

MVP:

Maximal voiding pressure

PBS:

Phosphate buffered saline

PE:

Polyethylene

PVR:

Post-void residual urine volume

SD:

Standard deviation

S1PR2:

Sphingosine-1-phosphate receptor 2

SSEA-3:

Stage-specific embryonic antigen-3

TNFα:

Tissue necrotic factor α

TP:

Threshold pressure

UCB:

Umbilical cord blood

VEGF:

Vascular endothelial growth factor

References

  1. Homma Y, Akiyama Y, Tomoe H, Furuta A, Ueda T, Maeda D, et al. Clinical guidelines for interstitial cystitis/bladder pain syndrome. Int J Urol. 2020;27:578–89. https://doi.org/10.1111/iju.14234.

    Article  PubMed  Google Scholar 

  2. Maeda D, Akiyama Y, Morikawa T, Kunita A, Ota Y, Katoh H, et al. Hunner-type (classic) interstitial cystitis: a distinct inflammatory disorder characterized by pancystitis, with frequent expansion of clonal B-cells and epithelial denudation. PLoS One. 2015;10:e0143316. https://doi.org/10.1371/journal.pone.0143316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Furuta A, Suzuki Y, Igarashi T, Koike Y, Kimura T, Egawa S, et al. Angiogenesis in bladder tissues is strongly correlated with urinary frequency and bladder pain in patients with interstitial cystitis/bladder pain syndrome. Int J Urol. 2019;26(Suppl 1):35–40. https://doi.org/10.1111/iju.13972.

    Article  CAS  PubMed  Google Scholar 

  4. Xiao Y, Song YJ, Song B, Huang CB, Ling Q, Yu X. TGF-β/MAPK signaling mediates the effects of bone marrow mesenchymal stem cells on urinary control and interstitial cystitis after urinary bladder transplantation. Am J Transl Res. 2017;9:1193–202.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Song M, Lim J, Yu HY, Park J, Chun JY, Jeong J, et al. Mesenchymal stem cell therapy alleviates interstitial cystitis by activating Wnt signaling pathway. Stem Cells Dev. 2015;24:1648–57. https://doi.org/10.1089/scd.2014.0459.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kim A, Yu HY, Heo J, Song M, Shin JH, Lim J, et al. Mesenchymal stem cells protect against the tissue fibrosis of ketamine-induced cystitis in rat bladder. Sci Rep. 2016;6:30881. https://doi.org/10.1038/srep30881.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Furuta A, Yamamoto T, Igarashi T, Suzuki Y, Egawa S, Yoshimura N. 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. 2018;29:1615–22. https://doi.org/10.1007/s00192-018-3592-8.

    Article  PubMed  Google Scholar 

  8. Dezawa M. Muse cells provide the pluripotency of mesenchymal stem cells: direct contribution of Muse cells to tissue regeneration. Cell Transplant. 2016;25:849–61. https://doi.org/10.3727/096368916X690881.

    Article  PubMed  Google Scholar 

  9. Kuroda Y, Kitada M, Wakao S, Nishikawa K, Tanimura Y, Makinoshima H, et al. Unique multipotent cells in adult human mesenchymal cell populations. Proc Natl Acad Sci U S A. 2010;107:8639–43. https://doi.org/10.1073/pnas.0911647107.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kuroda Y, Kitada M, Wakao S, Dezawa M. Bone marrow mesenchymal cells: how do they contribute to tissue repair and are they really stem cells? Arch Immunol Ther Exp (Warsz). 2011;59:369–78. https://doi.org/10.1007/s00005-011-0139-9.

    Article  Google Scholar 

  11. Yamada Y, Wakao S, Kushida Y, Minatoguchi S, Mikami A, Higashi K, et al. S1P-S1PR2 axis mediates homing of Muse cells into damaged heart for long-lasting tissue repair and functional recovery after acute myocardial infarction. Circ Res. 2018;122:1069–83. https://doi.org/10.1161/CIRCRESAHA.117.311648.

    Article  CAS  PubMed  Google Scholar 

  12. Iseki M, Kushida Y, Wakao S, Akimoto T, Mizuma M, Motoi F, et al. Muse cells, nontumorigenic pluripotent-like stem cells, have liver regeneration capacity through specific homing and cell replacement in a mouse model of liver fibrosis. Cell Transplant. 2017;26:821–40. https://doi.org/10.3727/096368916X693662.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Uchida N, Kushida Y, Kitada M, Wakao S, Kumagai N, Kuroda Y, et al. Beneficial effects of systemically administered human Muse cells in adriamycin nephropathy. J Am Soc Nephrol. 2017;28:2946–60. https://doi.org/10.1681/ASN.2016070775.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shono Y, Kushida Y, Wakao S, Kuroda Y, Unno M, Kamei T, et al. Protection of liver sinusoids by intravenous administration of human Muse cells in a rat extra-small partial liver transplantation model. Am J Transplant. 2021;21:2025–39. https://doi.org/10.1111/ajt.16461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ozuru R, Wakao S, Tsuji T, Ohara N, Matsuba T, Amuran MY, et al. Rescue from Stx2-producing E. coli-associated encephalopathy by intravenous injection of Muse cells in NOD-SCID mice. Mol Ther. 2020;28:100–18. https://doi.org/10.1016/j.ymthe.2019.09.023.

    Article  CAS  PubMed  Google Scholar 

  16. Yabuki H, Wakao S, Kushida Y, Dezawa M, Okada Y. Human multilineage-differentiating stress-enduring cells exert pleiotropic effects to ameliorate acute lung ischemia-reperfusion injury in a rat model. Cell Transplant. 2018;27:979–93. https://doi.org/10.1177/0963689718761657.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Noda T, Nishigaki K, Minatoguchi S. Safety and efficacy of human Muse cell-based product for acute myocardial infarction in a first-in-human trial. Circ J. 2020;84:1189–92. https://doi.org/10.1253/circj.CJ-20-0307.

    Article  CAS  PubMed  Google Scholar 

  18. Fujita Y, Nohara T, Takashima S, Natsuga K, Adachi M, Yoshida K, et al. Intravenous allogeneic multilineage-differentiating stress-enduring cells in adults with dystrophic epidermolysis bullosa: a phase 1/2 open-label study. J Eur Acad Dermatol Venereol. 2021;35:e528–e31. https://doi.org/10.1111/jdv.17201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Funahashi Y, Yoshida M, Yamamoto T, Majima T, Takai S, Gotoh M. Intravesical application of rebamipide promotes urothelial healing in a rat cystitis model. J Urol. 2014;192:1864–70. https://doi.org/10.1016/j.juro.2014.06.081.

    Article  CAS  PubMed  Google Scholar 

  20. 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. https://doi.org/10.1002/nau.20777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Uchida H, Morita T, Niizuma K, Kushida Y, Kuroda Y, Wakao S, et al. Transplantation of unique subpopulation of fibroblasts, Muse cells, ameliorates experimental stroke possibly via robust neuronal differentiation. Stem Cells. 2016;34:160–73. https://doi.org/10.1002/stem.2206.

    Article  CAS  PubMed  Google Scholar 

  22. Fujita Y, Komatsu M, Lee SE, Kushida Y, Nakayama-Nishimura C, Matsumura W, et al. Intravenous injection of Muse cells as a potential therapeutic approach for epidermolysis bullosa. J Invest Dermatol. 2021;141:198–202.e6. https://doi.org/10.1016/j.jid.2020.05.092.

    Article  CAS  PubMed  Google Scholar 

  23. Kajitani T, Endo T, Iwabuchi N, Inoue T, Takahashi Y, Abe T, et al. Association of intravenous administration of human Muse cells with deficit amelioration in a rat model of spinal cord injury. J Neurosurg Spine. 2021;34(4):648–55. https://doi.org/10.3171/2020.7.SPINE20293.

    Article  PubMed  Google Scholar 

  24. Suzuki T, Sato Y, Kushida Y, Tsuji M, Wakao S, Ueda K, et al. Intravenously delivered multilineage-differentiating stress enduring cells dampen excessive glutamate metabolism and microglial activation in experimental perinatal hypoxic ischemic encephalopathy. J Cereb Blood Flow Metab. 2021;41:1707–20. https://doi.org/10.1177/0271678X20972656.

    Article  CAS  PubMed  Google Scholar 

  25. Yamashita T, Kushida Y, Wakao S, Tadokoro K, Nomura E, Omote Y, et al. Therapeutic benefit of Muse cells in a mouse model of amyotrophic lateral sclerosis. Sci Rep. 2020;10:17102. https://doi.org/10.1038/s41598-020-74216-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Furuta A, Jankowski RJ, Pruchnic R, Yoshimura N, Chancellor MB. The potential of muscle-derived stem cells for stress urinary incontinence. Expert Opin Biol Ther. 2007;7:1483–6. https://doi.org/10.1517/14712598.7.10.1483.

    Article  CAS  PubMed  Google Scholar 

  27. Kim A, Shin DM, Choo MS. Stem cell therapy for interstitial cystitis/bladder pain syndrome. Curr Urol Rep. 2016;17:1. https://doi.org/10.1007/s11934-015-0563-1.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank Chieko Yoshimoto and Atsuko Sasaki, who are research technicians at the department of Urology, Jikei University School of Medicine. This study was supported by JSPS KAKENHI Grant Number JP21K09382.

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Authors and Affiliations

  1. Department of Urology, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo, 105-8461, Japan

    Akira Furuta & Shin Egawa

  2. Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Yasumasa Kuroda & Mari Dezawa

  3. Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Tokunori Yamamoto

  4. Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Naoki Yoshimura

Authors
  1. Akira Furuta
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  2. Yasumasa Kuroda
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  3. Tokunori Yamamoto
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  4. Shin Egawa
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  5. Mari Dezawa
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  6. Naoki Yoshimura
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Contributions

A. Furuta: protocol, data collection, manuscript writing; Y. Kuroda: data collection; T. Yamamoto: management data analysis; S. Egawa: manuscript editing; M. Dezawa: manuscript editing; N. Yoshimura: protocol, management data analysis, manuscript editing.

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Correspondence to Akira Furuta.

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This study was supported by Life Science Institute, Inc.

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Furuta, A., Kuroda, Y., Yamamoto, T. et al. Effects of human Muse cells on bladder inflammation, overactivity, and nociception in a chemically induced Hunner-type interstitial cystitis-like rat model. Int Urogynecol J 33, 1293–1301 (2022). https://doi.org/10.1007/s00192-022-05166-w

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  • DOI: https://doi.org/10.1007/s00192-022-05166-w

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