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Discovering the process of bladder healing as the milestone for its regeneration

ABSTRACT: Molecular mechanism underlying regeneration process, triggered by stem cells in tissue engineered urinary bladder, is still poorly explained. The study aimed to explore underlining pathways associated with regeneration process in urinary bladder reconstructed with stem cell seeded graft. The study was performed on 110 Wistar rats. Urinary bladders were augmented with bladder acellular matrix (BAM)(n=52) or BAM seeded with adipose derived stem cells (ADSCs)(n=52). The process of bladder healing was analyzed at 7, 30, 90 and 180 days postoperatively. Gene expression was evaluated using microarrays and analyzed in GeneSpring Software. Gene ontology (GO) and pathway enrichment analyses of differentially expressed genes (DEGs) were performed. A total of 4023, 4674, 7997 and 1120 of DEGs between the bladders augmented with ADSCs seeded BAM and BAM only were identified at 7, 30, 90 and 180 days postoperatively, respectively. The DEGs were enriched in GO terms associated with cellular and intercellular events, morphogenesis, epithelium, smooth muscles and nerves regeneration, angiogenesis, inflammatory response and wound healing. Numerous differentially expressed pathways between the bladders augmented with ADSCs seeded BAM and BAM only were identified. In conclusion, this study provided the unequivocal evidence that stem cells changed healing milieu in tissue engineered urinary bladder and indicated underlying pathways that can be associated with regeneration process triggered by stem cells.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE103572 | GEO | 2017/09/07

SECONDARY ACCESSION(S): PRJNA401927

REPOSITORIES: GEO

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Project description:To date, there are no efficacious translational solutions for end-stage urinary bladder dysfunction. Current surgical strategies including urinary diversion and bladder augmentation enterocystoplasty (BAE) utilize autologous intestinal segments (e.g. ileum) to increase bladder capacity to protect renal function. Considered the standard of care, BAE is fraught with numerous short- and long-term clinical complications. Previous clinical trials employing tissue engineering approaches for bladder tissue regeneration have also been unable to translate bench-top findings into clinical practice. Major obstacles still persist which need to be overcome in order to advance tissue engineered products into the clinical arena. These include scaffold/bladder incongruencies, the acquisition and utlity of appropriate cells for anatomic and physiologic tissue recapitulation, and the choice of appropriate animal model for testing. Here we demonstrate that the elastomeric, bladder biomechanocompatible poly(1,8-octamethylene-citrate-co-octanol) (PRS; synthetic) scaffold co-seeded with autologous bone marrow-derived mesenchymal stem cells (MSCs) and CD34+ hematopoietic stem/progenitor cells (HSPCs) supports robust long-term, functional bladder tissue regeneration within the context of a clinically relevant baboon bladder augmentation model simulating bladder trauma. Partially cystectomized baboons were independently augmented with either autologous ileum or stem cell-seeded small intestinal submucosa (SIS; a commercially available biological scaffold) or PRS grafts. Stem cell synergism promoted functional tri-layer bladder tissue regeneration including whole graft neurovascularization in both cell-seeded grafts. However, PRS-augmented animals demonstrated fewer clinical complications and more advantageous tissue characterization metrics compared to ileum and SIS-augmented animals. Two-year study data demonstrate that PRS/stem cell-seeded grafts drive bladder tissue regeneration and are a suitable alternative to BAE.

Project description:Concentration- and time-dependent genomic changes in the mouse urinary bladder following exposure to arsenate in drinking water for up to twelve weeks. Inorganic arsenic (Asi) is a known human bladder carcinogen. The objective of this study was to examine the concentration dependence of the genomic response to Asi in the urinary bladders of mice. C57BL/6J mice were exposed for 1 or 12 weeks to arsenate in drinking water at concentrations of 0.5, 2, 10, and 50 mg As/L. Urinary bladders were analyzed using gene expression microarrays. A consistent reversal was observed in the direction of gene expression change: from predominantly decreased expression at 1 week to predominantly increased expression at 12 weeks. These results are consistent with evidence from in vitro studies of an acute adaptive response that is suppressed on longer exposure due to down-regulation of Fos. Pathways with the highest enrichment in gene expression changes were associated with epithelial-to-mesenchymal transition, inflammation, and proliferation. Benchmark dose (BMD) analysis determined that the lowest median BMD values for pathways were above 5 mg As/L, despite the fact that pathway enrichment was observed at the 0.5 mg As/L exposure concentration. This disparity may result from the non-monotonic nature of the concentration-responses for the expression changes of a number of genes, as evidenced by the much fewer gene expression changes at 2 mg As/L compared to lower or higher concentrations. Pathway categories with concentration-related gene expression changes included cellular morphogenesis, inflammation, apoptosis/survival, cell cycle control, and DNA damage response. The results of this study provide evidence of a concentration-dependent transition in the mode of action for the subchronic effects of Asi in mouse bladder cells in the vicinity of 2 mg Asi/L. Female C57Bl/J mice will be exposed to COLD Arsenate in drinking water. One week interium sac on 7/18/06. 100 samples including liver, lung, kidney and bladder. Bladder will be analyzed with microarrays, 24 samples. Twelve week terminal sac on 10/05/06. 75 total samples including lung, kidney, and bladder. Bladdler will be analyzed by microarray, 25 samples. Drinking water containing As will be prepared weekly with monitoring to determine amount used by mice. Following tissues will be available for genomic study: Bladder, liver, lung, and kidney.

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Discovering the process of bladder healing as the milestone for its regeneration

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