PMID- 30967358
OWN - NLM
STAT- MEDLINE
DCOM- 20200604
LR  - 20200604
IS  - 1873-4898 (Electronic)
IS  - 1477-5131 (Linking)
VI  - 15
IP  - 3
DP  - 2019 May
TI  - Mesenchymal stem cell therapy inhibited inflammatory and profibrotic pathways 
      induced by partial bladder outlet obstruction and prevented high-pressure urine 
      storage.
PG  - 254.e1-254.e10
LID - S1477-5131(19)30062-2 [pii]
LID - 10.1016/j.jpurol.2019.03.003 [doi]
AB  - BACKGROUND: Partial bladder outlet obstruction (pBOO) is characterized by an 
      initial inflammatory response that progresses to smooth muscle hypertrophy and 
      fibrosis. Current treatment modalities carry high risk of morbidity. Mesenchymal 
      stem cells (MSCs) are undifferentiated adult cells with reparative, 
      immunomodulatory, and anti-inflammatory capacities. The ability of MSCs to 
      inhibit inflammatory and profibrotic pathways in bladder cells has been recently 
      reported. OBJECTIVES: This study aimed to investigate the therapeutic effects of 
      MSCs on pBOO-induced inflammatory, profibrotic signaling pathways and end-organ 
      physiology. MATERIALS AND METHODS: Twenty Sprague Dawley rats were randomly 
      assigned to 5 groups: unobstructed controls, pBOO for 2 and 4 weeks, pBOO+MSCs 
      for 2 and 4 weeks. Partial bladder outlet obstruction was surgically induced 
      followed by intravenous injection of MSCs. Endpoint urodynamics was performed, 
      and bladder tissue harvested for analysis. Reverse transcription real time 
      polymerase chain reaction (RT-PCR) and immunohistochemistry were performed to 
      study gene and protein expression of major inflammatory and profibrotic markers. 
      RESULTS: Partial bladder outlet obstruction resulted in an upregulation of 
      transforming growth factor beta (TGFbeta1), mothers against decapentaplegic homolog 
      2/3 (SMAD2/3), hypoxia inducible factor 1 alpha (HIF1alpha), hypoxia inducible factor 
      3 alpha (HIF3alpha), vascular endothelial growth factor (VEGF), tumor necrosis factor 
      (TNFalpha), mechanistic target of rapamycin (mTOR), p70 ribosomal S6 protein kinase 
      (p70 S6K), collagen 1 (COL1), and collagen 3 (COL3) expression in a 
      time-dependent manner. This was coupled with a downregulation of interleukin 
      (IL)-10 expression. Increase of bladder fibrosis was directly related to the 
      duration of pBOO and associated with high urine storage pressure. Injected MSCs 
      were identified in the bladder 4 weeks after therapy. The immunomodulatory effect 
      of MSCs(defined by reduced TNFalpha and increased IL-10 and VEGF) was most 
      predominant 2 weeks after therapy. Significant downregulation of profibrotic 
      genes occurred 4 weeks after therapy. End filling pressure, hypertrophy, and 
      fibrosis were significantly reduced after MSC therapy (P < 0.05). DISCUSSION: 
      Mesenchymal stem cell therapy led to a profound systematic improvement of the 
      obstructed bladder. This included an initial anti-inflammatory response and a 
      subsequent antifibrotic reaction. Essentially, both phases were associated with a 
      reduction of urine storage pressure. The intravenously injected MSCs were tracked 
      in the bladder. However, their presence in non-target organs such as the lungs, 
      spleen, and liver was not tracked. CONCLUSIONS: Partial bladder outlet 
      obstruction induced significant upregulation of hypoxic, inflammatory, and 
      profibrotic markers. Mesenchymal stem cell therapy potently inhibited these 
      pathways and improved bladder function.
CI  - Copyright (c) 2019 Journal of Pediatric Urology Company. Published by Elsevier Ltd. 
      All rights reserved.
FAU - Wiafe, B
AU  - Wiafe B
AD  - Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, 
      Canada.
FAU - Adesida, A B
AU  - Adesida AB
AD  - Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, 
      Canada.
FAU - Churchill, T
AU  - Churchill T
AD  - Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, 
      Canada.
FAU - Kadam, R
AU  - Kadam R
AD  - Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, 
      Canada.
FAU - Carleton, J
AU  - Carleton J
AD  - Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, 
      Canada.
FAU - Metcalfe, P D
AU  - Metcalfe PD
AD  - Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, 
      Canada. Electronic address: pmetcalf@ualberta.ca.
LA  - eng
PT  - Journal Article
DEP - 20190312
PL  - England
TA  - J Pediatr Urol
JT  - Journal of pediatric urology
JID - 101233150
SB  - IM
MH  - Animals
MH  - Female
MH  - Fibrosis/etiology/prevention & control
MH  - Inflammation/etiology/prevention & control
MH  - *Mesenchymal Stem Cell Transplantation
MH  - Random Allocation
MH  - Rats, Sprague-Dawley
MH  - Urinary Bladder/pathology/*physiopathology
MH  - Urinary Bladder Neck Obstruction/complications/*surgery
MH  - Urine
OTO - NOTNLM
OT  - Anti-fibrotic
OT  - Anti-inflammatory
OT  - Hypoxia
OT  - Mesenchymal stem cell therapy
OT  - Partial bladder outlet obstruction
EDAT- 2019/04/11 06:00
MHDA- 2020/06/05 06:00
CRDT- 2019/04/11 06:00
PHST- 2018/11/23 00:00 [received]
PHST- 2019/03/03 00:00 [accepted]
PHST- 2019/04/11 06:00 [pubmed]
PHST- 2020/06/05 06:00 [medline]
PHST- 2019/04/11 06:00 [entrez]
AID - S1477-5131(19)30062-2 [pii]
AID - 10.1016/j.jpurol.2019.03.003 [doi]
PST - ppublish
SO  - J Pediatr Urol. 2019 May;15(3):254.e1-254.e10. doi: 10.1016/j.jpurol.2019.03.003. 
      Epub 2019 Mar 12.