PMID- 35663428 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220716 IS - 1662-5102 (Print) IS - 1662-5102 (Electronic) IS - 1662-5102 (Linking) VI - 16 DP - 2022 TI - Brain-Derived Neurotrophic Factor Is an Important Therapeutic Factor in Mesenchymal Stem Cell Secretions for Treatment of Traumatic Peripheral Pelvic Injuries. PG - 866094 LID - 10.3389/fncel.2022.866094 [doi] LID - 866094 AB - Traumatic neuromuscular injury to the pudendal nerve and urethra during childbirth does not regenerate well and contributes to stress urinary incontinence in women. Mesenchymal stem cells (MSCs) can improve neuroregeneration via their secretions, or secretome, which includes brain-derived neurotrophic factor (BDNF). In this study, we investigated whether BDNF is a key factor in the secretome of MSCs for the facilitation of functional recovery following a dual simulated childbirth injury. BDNF knockdown (KD) MSCs were created using an anti-BDNF shRNA lentivirus vector. A scrambled sequence was used as a transduction control (scrambled). Cells were cultured for 24 h before media was concentrated 50x to create concentrated conditioned media (CCM) containing MSC secretome. CCM of unmanipulated MSCs was screened for high BDNF expression (high BDNF CCM). Concentrated control media (CM) was created by concentrating media not conditioned by cells. Female Sprague-Dawley rats underwent bilateral pudendal nerve crush and vaginal distension (Injury) or sham injury. One hour and 1 week after injury, sham injured rats received CM, and injured rats received CM, high BDNF CCM, KD CCM, or scrambled CCM (300 mul intraperitoneally). Three weeks after injury, rats underwent leak point pressure (LPP) and pudendal nerve sensory branch potential (PNSBP) recordings. The urethra and pudendal nerve were harvested for anatomical assessment. ANOVA followed by the Student-Newman-Keuls test determined significant differences between groups (p < 0.05). BDNF KD CCM had significantly decreased BDNF concentration compared to scrambled CCM, while the concentration in high BDNF CCM was significantly increased. LPP was significantly decreased in CM and KD CCM treated animals compared to sham injury, but not with scrambled or high BDNF CCM. PNSBP firing rate showed a significant decrease with CM treatment compared to sham injury. Neuromuscular junctions in the urethral sphincter in KD CCM, scrambled CCM, and high BDNF CCM were healthier than CM treated rats. While anatomical and nerve function tests demonstrate regeneration of the pudendal nerve with any CCM treatment, LPP results suggest it takes longer to recover continence with reduced BDNF in CCM. BDNF in MSC CCM is an important factor for the acceleration of recovery from a dual nerve and muscle injury. CI - Copyright (c) 2022 Yuan, Balog, Lin, Hanzlicek, Kuang, Yan, Majerus and Damaser. FAU - Yuan, Xiaoyi AU - Yuan X AD - Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States. AD - Advanced Platform Technology Center, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, United States. AD - Department of Urology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China. FAU - Balog, Brian M AU - Balog BM AD - Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States. AD - Advanced Platform Technology Center, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, United States. AD - Department of Biology, University of Akron, Akron, OH, United States. FAU - Lin, Dan Li AU - Lin DL AD - Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States. AD - Advanced Platform Technology Center, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, United States. FAU - Hanzlicek, Brett AU - Hanzlicek B AD - Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States. AD - Advanced Platform Technology Center, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, United States. FAU - Kuang, Mei AU - Kuang M AD - Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States. FAU - Yan, Hao AU - Yan H AD - Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States. AD - Department of Urology, Xuanwu Hospital, Capital Medical University, Beijing, China. FAU - Majerus, Steve J A AU - Majerus SJA AD - Advanced Platform Technology Center, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, United States. FAU - Damaser, Margot S AU - Damaser MS AD - Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States. AD - Advanced Platform Technology Center, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, United States. AD - Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, United States. LA - eng PT - Journal Article DEP - 20220518 PL - Switzerland TA - Front Cell Neurosci JT - Frontiers in cellular neuroscience JID - 101477935 PMC - PMC9157419 OTO - NOTNLM OT - external urethral sphincter OT - leak point pressure OT - neuromuscular junctions OT - neuroregeneration OT - pudendal nerve OT - reinnervation OT - siRNA knockdown OT - urethra COIS- MD has an issued patent on MSC CCM treatment for genitourinary disorders, which is currently optioned for licensing. This study was performed with grant funding prior to optioning the intellectual property and involved no corporate input or influence. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/06/07 06:00 MHDA- 2022/06/07 06:01 PMCR- 2022/01/01 CRDT- 2022/06/06 13:59 PHST- 2022/01/30 00:00 [received] PHST- 2022/04/12 00:00 [accepted] PHST- 2022/06/06 13:59 [entrez] PHST- 2022/06/07 06:00 [pubmed] PHST- 2022/06/07 06:01 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fncel.2022.866094 [doi] PST - epublish SO - Front Cell Neurosci. 2022 May 18;16:866094. doi: 10.3389/fncel.2022.866094. eCollection 2022.