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VEGF overexpressed mesoangioblasts enhance urethral and vaginal recovery following simulated vaginal birth in rats

ABSTRACT: Background: Vaginal birth causes injury to the pelvic floor and may lead to urinary incontinence. Cell therapy has been proposed to assist in functional recovery. Objective: To assess if intra-arterial injection of mesoangioblasts (MABs) or Vascular Endothelial Growth Factor (VEGF)-overexpressed MABs, improves urethral and vaginal function recovery after simulated vaginal delivery (SVD). Results: All stem-cell injected rats had external urethral sphincteric and vaginal function recovery within 14d, as compared to half of controls. Functional recovery was paralleled by improved muscle regeneration and microvascularization. Recovery was not different between autologous and allogenic MABs. MABsallo-VEGF accelerated functional recovery and increased GAP-43 expression at 7d. We detected early on in the recovery major transcriptional changes in both MABsallo and MABsallo-VEGF. MABSallo upregulated transcripts that encode proteins involved in myogenesis and dendrite development, and downregulated pro-inflammatory processes MABsallo-VEGF upregulated transcripts that encode proteins involved neuron and dendrite development and downregulates genes involved in hypoxia and oxidative stress. 7d after injury, Later MABsallo-VEGF showed a decrease in oxidative and inflammatory response compared to MABSallo treated urethras. These pathways are also downregulated in animals that have recovered at 7d, compared to non-recovered animals. Conclusion: Intra-arterial injection of MABsallo-VEGF enhances neuroregeneration and accelerates functional urethral and vaginal recovery after simulated vaginal delivery. Injection of stem cells induces faster recovery of urethral and vaginal function; cells overexpressing a factor increasing blood vessel formation, were even more effective.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE222561 | GEO | 2023/08/30

REPOSITORIES: GEO

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Project description:Periurethral human mesenchymal stem cell (hMSC) injections are associated with functional improvement in animal models of post-partum stress urinary incontinence (SUI). However, limited data exists on the role of hMSCs in modulating gene expression in tissue repair after urethral injury. We quantified temporal gene expression modulation in hMSCs, and injured rat urethral tissue, using RNA seq in an animal model of SUI, over a 3-day time period following urethral injury, and local hMSC therapy. We injected PKH fluorescent-labeled human hMSC into the periurethral space of rats, following a 4h vaginal distention (3 rats per time point). Control rats underwent vaginal distention injury only, and were sacrificed at 12h, 24h, 36h, 72h post injury. Rat urethral and vaginal tissues were frozen and sectioned. Fluorescent labeled hMSCs were distinguished from adjacent, unlabeled rat urethral tissue. RNA was prepared from urethral tissue obtained by laser dissection of frozen tissue sections and sequenced on an Illumina HiSeq 2500. Differentially expressed genes (DEGs) over 72h were evaluated using a 2-group t-test (p<0.05). Our transcriptional analyses identified candidate genes involved in tissue injury, that were broadly sorted by injury and exposure to hMSC, throughout the first 72h of acute phase of injury. DEGs in treated urethra, compared with untreated urethra, were functionally associated with tissue repair, angiogenesis, neurogenesis, and oxidative stress suppression. DEGs included a variety of cytokines, extracellular matrix stabilization and regeneration genes, cytokine signaling modification, cell cycle regulation, muscle differentiation and stabilization. Moreover, our results revealed DEGs changes in the hMSCs (PKH-labelled), which were harvested from injured urethra. The expressions are related to DNA damage repair, transcription activation, stem cell regulation, cell survival, apoptosis, self-renewal, cell proliferation, migration and injury response.

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VEGF overexpressed mesoangioblasts enhance urethral and vaginal recovery following simulated vaginal birth in rats

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