Improved bladder contractility after transplantation of human mesenchymal stem cells overexpressing hepatocyte growth factor into underactive bladder from bladder outlet obstruction models of rats

PLoS One. 2021 Dec 22;16(12):e0261402. doi: 10.1371/journal.pone.0261402. eCollection 2021.

Abstract

Introduction: An underactive bladder can lead to difficulty in voiding that causes incomplete emptying of the bladder, suggesting the need for a new strategy to increase bladder contractility in such patients. This study was performed to investigate whether human mesenchymal stem cells (hMSCs) were capable of restoring bladder contractility in rats with underactive bladder due to bladder outlet obstruction (BOO) and enhancing their effects by overexpressing hepatocyte growth factor (HGF) in hMSCs.

Materials and methods: The hMSCs were transplanted into the bladder wall of rats. Fifty female Sprague-Dawley rats at six weeks of age were divided into five groups: group 1: control; group 2: sham intervention; group 3: eight-week BOO; group 4: BOO rats transplanted with hMSCs; and group 5: BOO rats transplanted with hMSCs overexpressing HGF. Two weeks after the onset of BOO in groups 4 and 5, hMSCs were injected into the bladder wall. Cystometry evaluation was followed by Masson's trichrome staining of bladder tissues. Realtime PCR and immunohistochemical staining were performed to determine for hypoxia, apoptosis, and angiogenesis.

Results: Collagen deposition of bladder increased in BOO but decreased after transplantation of hMSCs. The increased inter-contraction interval and residual urine volume after BOO was reversed after hMSCs transplantation. The decreased maximal voiding pressure after BOO was restored by hMSCs treatment. The mRNA expression of bladder collagen1 and TGF-β1 increased in BOO but decreased after hMSCs transplantation. The decrease in vWF-positive cells in the bladder following BOO was increased after hMSCs transplantation. Caspase 3 and TUNEL-positive apoptosis of bladder cells increased in BOO but decreased after transplantation of hMSCs. These effects were enhanced by overexpressing HGF in hMSCs.

Conclusion: Transplantation of hMSCs into bladder wall increased the number of micro-vessels, decreased collagen deposition and apoptosis of detrusor muscle, and improved bladder underactivity. The effects were enhanced by overexpressing HGF in hMSCs. Our findings suggest that the restoration of underactive bladder using hMSCs may be used to rectify micturition disorders in patients following resolution of BOO. Further studies are needed before hMSCs can be used in clinical applications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Collagen / genetics
  • Collagen / metabolism
  • Disease Models, Animal
  • Female
  • Hepatocyte Growth Factor / biosynthesis
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism*
  • Humans
  • Mesenchymal Stem Cell Transplantation*
  • Mesenchymal Stem Cells / physiology
  • Muscle Contraction / physiology
  • Neovascularization, Physiologic / physiology
  • RNA, Messenger / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Regeneration / physiology
  • Urinary Bladder / physiopathology*
  • Urinary Bladder Neck Obstruction / surgery*
  • Urinary Bladder, Underactive / surgery*
  • Urination / physiology

Substances

  • HGF protein, human
  • RNA, Messenger
  • Hepatocyte Growth Factor
  • Collagen

Grants and funding

This research was supported by a grant from Soonchunhyang University Research Fund and the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A2039317). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.