Stromal derived factor-1 plasmid as a novel injection for treatment of stress urinary incontinence in a rat model
Introduction and hypothesis
SDF-1 chemokine enhances tissue regeneration through stem cell chemotaxis, neovascularization and neuronal regeneration. We hypothesized that non-viral delivery of human plasmids that express SDF-1 (pSDF-1) may represent a novel regenerative therapy for stress urinary incontinence (SUI).
Seventy-six female rats underwent vaginal distention (VD). They were then divided into four groups according to treatment: pSDF-1 (n = 42), sham (n = 30), PBS (n = 1) and luciferase-tagged pSDF-1 (n = 3). Immediately after VD, the pSDF-1 group underwent immediate periurethral injection of pSDF-1, and the sham group received a vehicle injection followed by leak point pressure (LPP) measurement at the 4th, 7th and 14th days. Urogenital tissues were collected for histology. H&E and trichrome slides were analyzed for vascularity and collagen/muscle components of the sphincter. For the luciferase-tagged pSDF-1 group, bioluminescence scans (BLIs) were obtained on the 3rd, 7th and 14th days following injections. Statistical analysis was conducted using ANOVA with post hoc LSD tests. The Mann-Whitney U test was employed to make pair-wise comparisons between the treated and sham groups. We used IBM SPSS, version 22, for statistical analyses.
BLI showed high expression of luciferase-tagged pSDF-1 in the pelvic area over time. VD resulted in a decline of LPP at the 4th day in both groups. The pSDF1-treated group demonstrated accelerated recovery that was significantly higher than that of the sham-treated group at the 7th day (22.64 cmH2O versus 13.99 cmH2O, p < 0.001). Functional improvement persisted until the 14th day (30.51 cmH2O versus 24.11 cmH2O, p = 0.067). Vascularity density in the pSDF-1-treated group was higher than in the sham group at the 7th and 14th days (p < 0.05). The muscle density/sphincter area increased significantly from the 4th to 14th day only in the pSDF-1 group.
Periurethral injection of pSDF-1 after simulated childbirth accelerated the recovery of continence and regeneration of the urethral sphincter in a rat SUI model. This intervention can potentially be translated to the treatment of post-partum urinary incontinence.
KeywordsUrinary incontinence Parturition Chemokine CXCL12 Plasmids
CXC motif chemokine 12
institutional animal care and use committee
leak point pressure
mesenchymal stem cells
plasmid of SDF-1
skeletal muscle precursor cell
stress urinary incontinence
Juventus Therapeutics, Inc. provided the pSDF-1 for the experiments.
Preliminary data of part of this work were presented as a moderated poster at the American Urological Association meeting, San Diego, CA, 2016. (Reference: Khalifa A, Mahran A, Kavran M, Woda J, Penn M, Hijaz A (2016) MP65-01 stromal cell derived factor-1 accelerates recovery of continence in rat model of vaginal distension injury. J Urol 195 (4):e864. doi: https://doi.org/10.1016/j.juro.2016.02.1212).
Compliance with ethical standards
Conflicts of interest
Ahmad O. Khalifa: no conflict of interest; Michael Kavran: no conflict of interest; Amr Mahran: no conflict of interest; Ilaha Isali: no conflict of interest; Juliana Woda: former commercial developer of SDF-1 plasmid technology at Juventas Therapeutics; Chris A. Flask: no conflict of interest; Marc S. Penn: no conflict of interest; Adonis Hijaz: speaker for Astellas Pharma.
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