Mesenchymal stem cell therapy inhibited inflammatory and profibrotic pathways induced by partial bladder outlet obstruction and prevented high-pressure urine storage

Wiafe, Bridget; Adesida, Adetola B; Churchill, Thomas A.; Kadam, Rutuja; Carleton, Jennifer; Metcalfe, Peter

doi:10.1016/j.jpurol.2019.03.003

Cited by 18 publications

(20 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite numerous MSC-based therapies have been reported to improve function outcome of underactive bladder in rat models [36][37][38], a major limitation to the use of MSCs in clinical applications is their poor viability at the site of injury due to the hyperglycemia-induced ischemic microenvironment and to anoikis driven by the loss of cell adhesion. Therefore, to improve the longterm survival of the transplanted MSCs, strategies to regulate apoptotic signaling and enhance cell proliferation and adhesion have been developed, such as genetic modifications [39].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic effect of integrin-linked kinase gene-modified bone marrow-derived mesenchymal stem cells for streptozotocin-induced diabetic cystopathy in a rat model

et al. 2020

View full text Add to dashboard Cite

Background: Diabetic cystopathy (DCP) is a chronic complication of diabetes mainly within the submucosal and muscular layers of the bladder due to the hyperglycemia-induced ischemia. As no effective therapies are currently available, the administration of optimized mesenchymal stem cells (MSCs) provides a potential treatment of DCP. Thus far, new strategy, such as genetic modification of MSCs, has been developed and has shown promising outcomes of various disorders. Methods: This study was conducted using integrin-linked kinase (ILK) gene-modified bone marrow-derived stem cells (BMSCs) for streptozotocin (STZ)-induced diabetic cystopathy in a rat model. In total, 68 male Sprague-Dawley rats were randomized into five groups: sham control (control group, n = 10); DCP model alone (DM group, n = 10); DCP rats intravenously treated with BMSCs (BMSC group, n = 16); DCP rats accepted adenoviral vector-infected BMSCs (Ad-null-BMSC group, n = 16) and DCP rats accepted ILK adenoviral vector-infected BMSCs (Ad-ILK-BMSC group, n = 16). Diabetic rats accepted cell transplantation in the experimental group (2 rats per group) were sacrificed for the bladder tissue on the third day, 7th day, and 14th day of treatment respectively ahead of schedule. At 4 weeks after treatment, all rats in five groups accepted urodynamic studies to evaluate bladder function and were sacrificed for bladder tissue. Results: Our data showed that the underactive bladder function was significantly improved in DCP rats intravenously treated with ILK gene-modified BMSCs compared to those in the DM, BMSCs, and Ad-null-BMSC group. Meanwhile, we found that gene-modified BMSC treatment significantly promoted the activation of the AKT/ GSK-3β pathway by increasing phosphorylation and led to the enhancement of survival. In addition, the expression levels of angiogenesis-related protein vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and stromal cell-derived factor-1 (SDF-1) were significantly higher in the Ad-ILK-BMSC group than that in the DM, BMSCs, and Ad-null-BMSC group as assessed by enzyme-linked immunosorbent assay and western blot. As two indicators of vascular endothelial cell markers, the expression of von Willebrand factor (vWF) and CD31 by

show abstract

Section: Discussionmentioning

confidence: 99%

Therapeutic effect of integrin-linked kinase gene-modified bone marrow-derived mesenchymal stem cells for streptozotocin-induced diabetic cystopathy in a rat model

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Our previous investigation using the same animal population demonstrated that obstruction upregulates the gene expression of TGF-β1 -a master-inducer capable of sustaining the entire EMT process. 11 Additionally, our lab previously confirmed the transcriptional upregulation of SMAD2/3 alongside increased protein expression of phosphorylated SMAD2/3 in bladder urothelium after pBOO. 11 The TGF-β1-SMAD2/3 pathway is closely tied to myofibroblast differentiation 16 and EMT.…”

Section: Discussionmentioning

confidence: 53%

“…11 Additionally, our lab previously confirmed the transcriptional upregulation of SMAD2/3 alongside increased protein expression of phosphorylated SMAD2/3 in bladder urothelium after pBOO. 11 The TGF-β1-SMAD2/3 pathway is closely tied to myofibroblast differentiation 16 and EMT. 15 Specifically, the phosphorylated SMAD2/3 combine with SMAD4 to form a heterotrimer complex which translocates to the nucleus to regulate gene expression and generate myofibroblasts.…”

Section: Discussionmentioning

confidence: 53%

“…Rats in pBOO groups underwent urethral ligation under isoflurane anesthesia to create partial bladder outlet obstruction as described earlier. 2,11 In sum, the bladder was exposed, and an 18gauge angiocatheter was inserted into the urethra. A 2-0 silk suture was then tied around the urethra, and the catheter was removed.…”

Section: Induction Of Pboomentioning

confidence: 99%

“…6,7,8 Concerning pBOO, we have previously demonstrated the anti-inflammatory and anti-fibrotic effects of MSC treatment in-vitro using hypoxic bladder smooth muscle cells, and in-vivo using acute and long-term pBOO rat models. 9,10,11 Since MSC therapy for pBOO holds great promise, it necessitates a fuller understanding of the underlying mechanisms that drive pBOO and the effect that MSCs have on them.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mesenchymal stem cells ameliorate partial bladder outlet obstruction-induced epithelial-mesenchymal transition type II independent of mast cell recruitment and degranulation

Kadam

Wiafe

Metcalfe

2020

CUAJ

View full text Add to dashboard Cite

Introduction: Partial bladder outlet obstruction (pBOO) results in increased urinary storage pressure and significant morbidity. Increased pressure results in a sequence of programmed events: an initial inflammatory phase, smooth muscle hypertrophy, and fibrosis. Although epithelial-mesenchymal transition (EMT) and mast cell accumulation play intermediary roles in some fibrotic conditions, their role in pBOO has not yet been elucidated. Mesenchymal stem cell (MSC) therapy is emerging as a promising treatment for several conditions. It potently inhibits bladder deterioration after pBOO; however, its mechanism of action is insufficiently understood. Thus, we hypothesize that EMT type II pathway plays a significant role in pBOO, aided by the recruitment and activation of mast cells, and these are potently inhibited by MSCs. Methods: PBOO was surgically induced in female Sprague-Dawley rats and simultaneously treated with MSCs. Treatment effect was determined after two or four weeks, and compared to untreated controls. Immunohistochemistry was used to measure markers characteristic of EMT (vimentin, collagenase, and collagen). Whole and degranulated mast cell counts were also performed. Results: PBOO resulted in an increased expression of collagenase, vimentin, and collagen. Mast cell recruitment increased proportionately to the length of bladder obstruction. MSC treatment significantly mitigated the EMT type II response, but mast cell recruitment and degranulation were unaffected. Conclusions: Our results demonstrate the involvement of EMT type II in the pathophysiology of pBOO and confirm its mitigation with MSC treatment independent of mast cells response. The observations provide insight into the mechanism of action and have therapeutic ramifications.

show abstract

Valve Bladder Syndrome Associated with Posterior Urethral Valves: Natural History, Work-up, and Management

Chan

Wang

Davé

2020

Curr Bladder Dysfunct Rep

View full text Add to dashboard Cite

Mesenchymal stem cell therapy inhibited inflammatory and profibrotic pathways induced by partial bladder outlet obstruction and prevented high-pressure urine storage

Cited by 18 publications

References 23 publications

Therapeutic effect of integrin-linked kinase gene-modified bone marrow-derived mesenchymal stem cells for streptozotocin-induced diabetic cystopathy in a rat model

Therapeutic effect of integrin-linked kinase gene-modified bone marrow-derived mesenchymal stem cells for streptozotocin-induced diabetic cystopathy in a rat model

Mesenchymal stem cells ameliorate partial bladder outlet obstruction-induced epithelial-mesenchymal transition type II independent of mast cell recruitment and degranulation

Valve Bladder Syndrome Associated with Posterior Urethral Valves: Natural History, Work-up, and Management

Contact Info

Product

Resources

About