Therapeutic effect of adipose stromal vascular fraction spheroids for partial bladder outlet obstruction induced underactive bladder

Abstract Background: Underactive bladder (UAB) is a common clinical problem but related research is rarely explored. As there are currently no effective therapies, the administration of adipose stromal vascular fraction (ad-SVF) provides a new potential method to treat underactive bladder. Methods: Male Sprague-Dawley rats were induced by partial bladder outlet obstruction (PBOO) for four weeks and randomly divided into three groups: rats treated with PBS (Sham group); rats administrated with ad-SVF (ad-SVF group) and rats performed with ad-SVF spheroids (ad-SVFsp group). After four weeks, urodynamic studies were performed to evaluate bladder functions and all rats were sacrificed for further studies.Results: We observed that the bladder functions and symptoms of UAB were significantly improved in the ad-SVFsp group than that in the Sham group and ad-SVF group. Meanwhile, our data showed that ad-SVF spheroids could remarkably promote angiogenesis, suppress cell apoptosis and stimulate cell proliferation in bladder tissue than that in the other two groups. Moreover, ad-SVF spheroids increased the expression levels of bFGF, HGF and VEGF-A than ad-SVF. IVIS Spectrum small-animal in vivo imaging system revealed that ad-SVF spheroids could increase the retention rate of transplanted cells in bladder tissue. Conclusions: Ad-SVF spheroids improved functions and symptoms of bladder induced by PBOO, which contributes to promote angiogenesis, suppress cell apoptosis and stimulate cell proliferation. Ad-SVF spheroids provide a potential treatment for the future patients with UAB.

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Human Urine-derived Stem Cells Improve Partial Bladder Outlet Obstruction in Rats: Preliminary Data and microRNA-mRNA Expression Profile

10.21203/rs.3.rs-838807/v1 ◽

2021 ◽

Author(s):

Menjiang Tu ◽

Rui Wang ◽

Pei Zhu ◽

Qingqing Wang ◽

Bishao Sun ◽

...

Keyword(s):

Mrna Expression ◽

Bladder Outlet Obstruction ◽

Bioinformatics Analysis ◽

Therapy Group ◽

Expression Profiles ◽

Outlet Obstruction ◽

Bladder Function ◽

Detrusor Muscle ◽

Bladder Tissue ◽

Partial Bladder Outlet Obstruction

Abstract Background: Partial bladder outlet obstruction (pBOO), a common urological disease, often results in bladder tissue inflammation and remodeling. Human urine-derived stem cells (USCs) have demonstrated therapeutic benefits in various organ injury models. We used a rat model of pBOO to investigate the effect of USCs on bladder function and to explore the miRNA and gene expression profiles in bladder tissue using RNA sequencing.Methods: In total, 18 rats were randomly and evenly assigned to the following three groups: a sham surgery group, a pBOO without USC therapy group, and a pBOO with USC therapy group (subjected to treatment with USCs six times every other week). All rats were subjected to routine urodynamic monitoring. Detrusor muscle strips were analyzed and pathophysiology was assessed. Finally, altered miRNA and mRNA expression profiles of bladder tissue were examined using RNA sequencing and bioinformatics analysis technology.Results: After USC treatment, urodynamic monitoring revealed elevated bladder compliance and maximal voiding pressure, declined end filling pressure and voided volume, and improved detrusor muscle contractility and carbachol sensitivity in pBOO rats. Histology and TUNEL assay revealed reduced collagen deposition and muscle cell apoptosis in bladder tissue. The differential expression of eight miRNAs in pBOO rats was reversed by USC treatment. Bioinformatics analysis helped identify miR-142 and miR-9a as the two largest nodes of differentially expressed miRNAs in the miRNA‑gene interaction network in the USC-treated group. The Kyoto Encyclopedia of Genes and Genomes analysis revealed enrichment of multiple significant pathways, including those involved in necroptosis and cytokine-cytokine receptor interactions.Conclusions: This is the first study to reveal the protective effect of USCs on bladder function and bladder remodeling in pBOO rats. The miRNA and mRNA expression levels differed in the bladder of pBOO rats with and without USC treatment. Although the mechanism underlying these effects has not been fully elucidated, necroptosis and cytokine-cytokine receptor interaction-related pathways may be involved.

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Compensatory paracrine mechanisms that define the urothelial response to injury in partial bladder outlet obstruction

AJP Renal Physiology ◽

10.1152/ajprenal.00006.2007 ◽

2007 ◽

Vol 293 (4) ◽

pp. F1147-F1156 ◽

Cited By ~ 6

Author(s):

Thomas S. Lendvay ◽

Robert Sweet ◽

Chang-Hee Han ◽

Tarkan Soygur ◽

Jan-Fan Cheng ◽

...

Keyword(s):

Cell Proliferation ◽

Bladder Outlet Obstruction ◽

Outlet Obstruction ◽

Urothelial Cell ◽

Chromosome 9 ◽

Transitional Epithelium ◽

Urothelial Cells ◽

Wild Type ◽

Partial Bladder Outlet Obstruction ◽

Significant Difference

Diseases and conditions affecting the lower urinary tract are a leading cause of dysfunctional sexual health, incontinence, infection, and kidney failure. The growth, differentiation, and repair of the bladder's epithelial lining are regulated, in part, by fibroblast growth factor (FGF)-7 and -10 via a paracrine cascade originating in the mesenchyme (lamina propria) and targeting the receptor for FGF-7 and -10 within the transitional epithelium (urothelium). The FGF-7 gene is located at the 15q15-q21.1 locus on chromosome 15 and four exons generate a 3.852-kb mRNA. Five duplicated FGF-7 gene sequences that localized to chromosome 9 were predicted not to generate functional protein products, thus validating the use of FGF-7-null mice as an experimental model. Recombinant FGF-7 and -10 induced proliferation of human urothelial cells in vitro and transitional epithelium of wild-type and FGF-7-null mice in vivo. To determine the extent that induction of urothelial cell proliferation during the bladder response to injury is dependent on FGF-7, an animal model of partial bladder outlet obstruction was developed. Unbiased stereology was used to measure the percentage of proliferating urothelial cells between obstructed groups of wild-type and FGF-7-null mice. The stereological analysis indicated that a statistical significant difference did not exist between the two groups, suggesting that FGF-7 is not essential for urothelial cell proliferation in response to partial outlet obstruction. In contrast, a significant increase in FGF-10 expression was observed in the obstructed FGF-7-null group, indicating that the compensatory pathway that functions in this model results in urothelial repair.

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miRNA-325-3p overexpression mitigates partial bladder outlet obstruction (PBOO) by regulating the TLR4/NF-κB(p65) pathway

Archives of Medical Science ◽

10.5114/aoms/140353 ◽

2021 ◽

Author(s):

Zhaofei Liu ◽

Yiduo Zhou ◽

Ziyang Liu ◽

Yi Huang ◽

Jie Gao ◽

...

Keyword(s):

Cell Proliferation ◽

Noncoding Rna ◽

Bladder Outlet Obstruction ◽

Cell Model ◽

Outlet Obstruction ◽

Model Group ◽

Prostate Hyperplasia ◽

Partial Bladder Outlet Obstruction ◽

Protein Expressions

IntroductionThe microRNA (miRNA) is a noncoding RNA that plays an important role in many diseases. Partial bladder outlet obstruction (PBOO) is a blockage between the outlet of the neck of the bladder and the external urethral orifice secondary to prostate hyperplasia and urethral stricture, and causative of morphological and functional abnormalities in the bladder. We examine the effects of miRNA-325-3p on PBOO and related mechanisms through an in-vitro study.Material and methodsPrimary BSMCs were extracted from SD rats and subjected to TGF-β1 stimulation to form a cell model of PBOO. Cell proliferation was measured by CCK-8 assay, and the gene and protein expressions were measured by RT-qPCR, western blot, and immunofluorescence. The correlation between miRNA-325-3p and ILK was analyzed through a double-luciferase target experiment.ResultsThe proliferation of BSMCs in the model group increased more significantly than in the normal group (P<0.001) with miRNA-325-3p repression, and led to the activation of ILK and the TLR4/NF-κB(p65) pathway as well as significant changes in the marker proteins. With miRNA-325-3p transfection, the rate of cell proliferation of the miRNA-325-3p group was significantly suppressed with ILK repression compared with that of the model group, and led to the suppression of TLR4/NF-κB(p65) activity and the regulation of protein expressions. However, the miRNA-325-3p treatment’s effects disappeared as ILK was supplemented. The double-luciferase experiment helped miRNA-325-3p target ILK in BSMCs.ConclusionsmiRNA-325-3p overexpression may play a key role in PBOO-induced cell proliferation by targeting ILK and suppressing the TLR4/NF-κB(p65) signaling pathway.

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Human Urine-derived Stem Cells Improve Bladder Function After Partial Bladder Outlet Obstruction: Preliminary Data and the microRNA–mRNA Expression Profile of Bladder Tissue

10.21203/rs.3.rs-614750/v1 ◽

2021 ◽

Author(s):

Menjiang Tu ◽

Rui Wang ◽

Pei Zhu ◽

Qingqing Wang ◽

Bishao Sun ◽

...

Keyword(s):

Stem Cells ◽

Mrna Expression ◽

Bladder Outlet Obstruction ◽

Therapy Group ◽

Expression Profiles ◽

Outlet Obstruction ◽

Bioinformatic Analysis ◽

Bladder Function ◽

Bladder Tissue ◽

Partial Bladder Outlet Obstruction

Abstract Background: Partial bladder outlet obstruction (pBOO), a common urological disease, often results in bladder tissue inflammation and tissue remodeling. Human urine-derived stem cells (hUSCs) have shown therapeutic benefits in various organ injury models. We used a rat model to investigate the effect of hUSCs on bladder function in pBOO rats and explore the miRNA and gene expression profiles in bladder tissue using RNA-sequencing.Methods: In total, 18 rats were randomly and evenly assigned to three groups: a sham surgery group, a pBOO without USCs therapy group, and a pBOO with USCs therapy group (treated with hUSCs six times every other week). All rats were subjected to routine urodynamic monitoring. Detrusor muscle strips were evaluated and pathophysiology was assessed. Finally, altered miRNA and mRNA expression profiles of bladder tissue were examined using RNA-sequencing and bioinformatic analysis technology.Results: After USC treatment, urodynamic monitoring revealed elevated bladder compliance and maximal voiding pressure, declined end filling pressure and voided volume, and improved detrusor contractility and carbachol sensitivity in pBOO rats. Histology and TUNEL assay showed reduced collagen deposition and muscle cell apoptosis in bladder tissue. The differential expression of eight miRNAs in pBOO rats was reversed by USC treatment. Bioinformatic analysis identified miR-142 and miR-9a as the two largest nodes of differentially expressed miRNAs in the miRNA‑gene interaction network. The Kyoto Encyclopedia of Genes and Genomes analysis revealed enrichment of multiple significant pathways, including those involved in necroptosis and cytokine-cytokine receptor interactions.Conclusions: This is the first study to reveal the protective effect of hUSCs on bladder function and bladder remodeling in pBOO rats. The miRNA and mRNA expression levels differed in the bladder of pBOO rats with and without USC treatment. Although the mechanism underlying these effects have not been fully elucidated, necroptosis and cytokine-cytokine receptor interaction related pathways may be involved.

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