A Dual Nerve and Muscle Injury is Partial Recovered with Brain-Derived Neurotrophic Factor Stem Cell treatment
Brian Michael Balog, B.S.1,2,3; Xiaoyi Yuan, M.D.4; Dan Li Lin, M.D.5; Mei Kuang, Ph.D.1; Brett Hanzlicek, M.S.6; Hao Yan, M.D.7; Margot Damaser, Ph.D.8; (1)Cleveland Clinic Lerner Research Institute, Cleveland, OH, (2)Louis Stokes Veteran Service Hospital, Cleveland, OH, (3)University of Akron, Akron, OH, (4)Tongji Hospital Huazhong University of Science and Technology, Hankou, Wuhan, China, (5)Louis Stokes Veteran Affairs Medical Center, Cleveland, OH, (6)Louis Stokes Veterans Affairs Medical Center, Cleveland, OH, (7)Xuanwu Hospital Capital Medical Universty, Beijing Shi, China, (8)Louis Stokes Veteran Affairs Hopsital, Cleveland, OH
Stress urinary incontinence (SUI) is highly correlated with childbirth when the pudendal nerve and the muscle it innervates, the external urethral sphincter, are both injured, creating a dual muscle & nerve injury. While neuroregeneration is promoted by brain-derived neurotrophic factor (BDNF), BDNF inhibits myogenesis. Mesenchymal stem cell (MSC) secretions contain BDNF and accelerate recovery in a SUI rat model. We hypothesize that BDNF is the active factor in accelerated recovery via MSC secretions.
An anti-BDNF shRNA lentivirus vector was used to create BDNF Knockdown (KD) rat bone marrow-derived MSCs. A scrambled sequence (scrambled) served as a transfection control. Media was sorted and concentrated 50x to produce concentrated conditioned media (CCM) containing the secretions of MSCs. Media that was not conditioned by the cells served as concentrated control media (CM). Rats underwent either sham injury (SI) or pudendal nerve crush (PNC) & vaginal distension (VD) as a model of SUI. CCM or CM (300Ál) was injected intraperitoneally 1 hour and 1 week after the injury. SI rats received CM; PNC+VD rats received CM, CCM, KD CCM or scrambled CCM. Leak point pressure (LPP) and pudendal nerve sensory branch potential (PNSBP) were recorded three weeks after injury. The urethra and pudendal nerve were harvested for anatomic assessment. ANOVA followed by a Student-Newman-Keuls posthoc test was used to determine statistically significant differences between groups (p<0.05).
LPP was not significantly decreased in scrambled (36.0 ▒ 3.1 cm H2O) or CCM (51.1 ▒ 3.1 cm H2O) groups compared to SI (40.9 ▒ 3.3 cm H2O), but was significantly decreased in PNC+VD + CM (28.3 ▒ 2.1 cm H2O) and KD CCM (31.1 ▒ 2.5 cm H2O) groups. CM treatment of PNC+VD (399 ▒ 100 Hz) was the only group with a significant decrease in PNSBP firing rate compared to SI (977 ▒ 93 Hz). KD CCM, scrambled CCM, and CCM treated PNC+VD groups showed healthier neuromuscular junctions in the external urethral sphincter compared to PNC+VD+CM. However, pudendal nerve axons were less dense with PNC+VD treated with KD CCM than other treatment groups.
Reducing BDNF in CCM reduces neuroregeneration of the pudendal nerve and LPP after PNC+VD, but does not reduce pudendal nerve firing rate or neuromuscular junction recovery, suggesting that complete recovery is likely slowed with reduced BDNF. BDNF is most likely not the only factor important for recovery from the dual nerve and muscle injury of childbirth that results in SUI.
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