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

Furuta A1, Kuroda Y2, Igarashi T1, Kimura T1, Suzuki Y3, Egawa S1, Dezawa M2, Yoshimura N4

Research Type

Pure and Applied Science / Translational

Abstract Category

Pelvic Pain Syndromes

Abstract 28
Live Pure and Applied Science 2 - Pain, Pharma, Pathophysiology
Scientific Podium Session 4
Friday 15th October 2021
09:30 - 09:40
Live Room 1
Animal Study Painful Bladder Syndrome/Interstitial Cystitis (IC) Basic Science Stem Cells / Tissue Engineering
1. Department of Urology, Jikei University School of Medicine, Tokyo, Japan, 2. Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan, 3. Department of Urology, Tokyo Metropolitan Rehabilitation Hospital, Tokyo, Japan, 4. Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
Presenter
Links

Abstract

Hypothesis / aims of study
Human multilineage-differentiating stress enduring (Muse) cells, a novel nontumorigenic pluripotent-like stem cell population, reside in the bone marrow, skin and adipose tissues, and can be collected as cells positive for stage-specific embryonic antigen-3 (SSEA-3), a surface marker for human embryonic stem cells. There are approximately 1% of SSEA-3-positive Muse cells in bone marrow-derived mesenchymal stem cells (BM-MSCs) [Ref.1]. Thus, we investigated the effects of locally administered human Muse cells on bladder tissues, function and nociceptive behavior in a chemically induced interstitial cystitis (IC)-like rat model.
Study design, materials and methods
Chemical cystitis was induced by intravesical instillation of 0.2N hydrochloride (HCl) for 15 minutes in female F344 rats. Muse cells, non-Muse cells (BM-MSCs without Muse cells) or Hanks' balanced salt solution (HBSS) (vehicle) were injected into the anterior and posterior bladder wall at each 1x10^4 cells/10μL 6 hours after HCl application whereas controls received bladder wall injection of HBSS without HCl instillation. Changes in urinary frequency were evaluated before and 1 week after the injection using metabolic cages. In addition, nociceptive behavior (freezing) induced by intravesical instillation of 1mM capsaicin, and histological changes in expression of tissue necrotic factor α (TNFα) in the urothelium / lamina propria and c-Fos in the dorsal horn of L6 spinal cord were examined 1 week after the injection in each group. In other animal groups, cystometrograms 1 week after the injection, and survival of Muse or non-Muse cells labelled by a fluorescent marker, mCherry in the bladder 1,2 and 4 weeks after the injection were also evaluated.
Results
There were significant increases in urinary frequency of vehicle and non-Muse cell groups, but not of the Muse cell group, compared with controls (Fig.1A). Significant increases in nociceptive behavior and expression of TNFα and c-Fos were observed in vehicle and non-Muse cell groups compared with controls whereas these significant changes were not seen in the Muse cell group (Fig.1B, C, D). In cystometrograms, bladder capacity was significantly decreased in vehicle and non-Muse cell groups, but not in the Muse cell group, compared with controls. In addition, a larger number of Muse cells survived in the urothelial basal layer or lamina propria compared with non-Muse cells until 4 weeks (Fig.2).
Interpretation of results
In the present study, human Muse cell treatment ameliorated bladder inflammation, bladder overactivity, and nociception in a rat model of chemically induced cystitis, as similarly reported in a previous study with bladder wall injection of rodent adipose-derived MSCs [Ref.2]. Currently, clinical trials using human Muse cell-product, CL2020 are ongoing for the treatments of myocardial infarction, cerebral infarction, spinal cord injury, epidermolysis bullosa, neonatal hypoxic-ischemic encephalopathy and amyotrophic lateral sclerosis.
Concluding message
These results indicate that locally administered human Muse cells significantly reduced bladder inflammation, resulting in improvement of bladder dysfunction such as urinary frequency and bladder pain in a chemically induced IC-like rat model. The Muse cell therapy could be a promising modality to treat IC, especially Hunner type IC with severe bladder pain due to chronic inflammation.
Figure 1
Figure 2
References
  1. Kuroda Y and Dezawa M, PNAS 107:8639--43, 2010
  2. Furuta A et al, Int Urogynecol J 29:1615-22, 2018
Disclosures
Funding This study was supported by JSPS KAKENHI Grant Number 15K10633. Clinical Trial No Subjects Animal Species Rat Ethics Committee the animal ethics committee of Jikei University School of Medicine
03/11/2024 12:49:33