{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T18:07:41Z","timestamp":1782497261942,"version":"3.54.5"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T00:00:00Z","timestamp":1652832000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["A1262R, 1 IK6 RX003843"],"award-info":[{"award-number":["A1262R, 1 IK6 RX003843"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>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 <jats:italic>via<\/jats:italic> 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 \u03bcl 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 (<jats:italic>p<\/jats:italic> &amp;lt; 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.<\/jats:p>","DOI":"10.3389\/fncel.2022.866094","type":"journal-article","created":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T04:46:11Z","timestamp":1652849171000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Brain-Derived Neurotrophic Factor Is an Important Therapeutic Factor in Mesenchymal Stem Cell Secretions for Treatment of Traumatic Peripheral Pelvic Injuries"],"prefix":"10.3389","volume":"16","author":[{"given":"Xiaoyi","family":"Yuan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian M.","family":"Balog","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan Li","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett","family":"Hanzlicek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Kuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve J. A.","family":"Majerus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margot S.","family":"Damaser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1002\/nau.10052","article-title":"The standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the international continence society","volume":"21","author":"Abrams","year":"2002","journal-title":"Neurourol. Urodyn."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.3727\/096368911X612477","article-title":"Lessons from genetically altered mesenchymal stem cells (MSCs): candidates for improved MSC-directed myocardial repair","volume":"21","author":"Alfaro","year":"2012","journal-title":"Cell Transplant."},{"key":"B3","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1002\/nau.22885","article-title":"Stress urinary incontinence and endogenous sex steroids in postmenopausal women","volume":"36","author":"Augoulea","year":"2017","journal-title":"Neurourol. Urodyn."},{"key":"B4","doi-asserted-by":"publisher","first-page":"113438","DOI":"10.1016\/j.expneurol.2020.113438","article-title":"The pudendal nerve motor branch regenerates via a brain derived neurotrophic factor mediated mechanism","volume":"334","author":"Balog","year":"2020","journal-title":"Exp. Neurol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"113781","DOI":"10.1016\/j.expneurol.2021.113781","article-title":"Brain derived neurotrophic factor mediates accelerated recovery of regenerative electrical stimulation in an animal model of stress urinary incontinence","volume":"343","author":"Balog","year":"2021","journal-title":"Exp. Neurol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1080\/14653240902849796","article-title":"Comparative characterization of bone marrow-derived mesenchymal stromal cells from four different rat strains","volume":"11","author":"Barzilay","year":"2009","journal-title":"Cytotherapy"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1016\/s0024-3205(01)01182-1","article-title":"Effects of anesthesia on cystometry and leak point pressure of the female rat","volume":"69","author":"Cannon","year":"2001","journal-title":"Life Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1016\/j.expneurol.2014.09.006","article-title":"Improving peripheral nerve regeneration: from molecular mechanisms to potential therapeutic targets","volume":"261","author":"Chan","year":"2014","journal-title":"Exp. Neurol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.expneurol.2005.10.029","article-title":"Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis","volume":"198","author":"Crigler","year":"2006","journal-title":"Exp. Neurol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1007\/s00192-018-3554-1","article-title":"Urinary incontinence in nulliparous women before and during pregnancy: prevalence, incidence, type and risk factors","volume":"29","author":"Daly","year":"2018","journal-title":"Int. Urogynecol. J."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2286","DOI":"10.1016\/j.juro.2008.01.098","article-title":"Stress urinary incontinence: relative importance of urethral support and urethral closure pressure","volume":"179","author":"Delancey","year":"2008","journal-title":"J. Urol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"20190020","DOI":"10.1098\/rsfs.2019.0020","article-title":"Daily bilateral pudendal nerve electrical stimulation improves recovery from stress urinary incontinence","volume":"9","author":"Deng","year":"2019","journal-title":"Interface Focus"},{"key":"B13","doi-asserted-by":"publisher","first-page":"F92","DOI":"10.1152\/ajprenal.00510.2014","article-title":"Mesenchymal stem cells and their secretome partially restore nerve and urethral function in a dual muscle and nerve injury stress urinary incontinence model","volume":"308","author":"Deng","year":"2015","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1395","DOI":"10.3727\/096368913X670921","article-title":"Rat mesenchymal stem cell secretome promotes elastogenesis and facilitates recovery from simulated childbirth injury","volume":"23","author":"Dissaranan","year":"2014","journal-title":"Cell Transplant."},{"key":"B15","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.ijgo.2006.04.042","article-title":"Postpartum evaluation of stress urinary incontinence among primiparas","volume":"94","author":"Eftekhar","year":"2006","journal-title":"Int. J. Gynaecol. Obstet."},{"key":"B16","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/j.expneurol.2007.01.040","article-title":"Electrical stimulation promotes sensory neuron regeneration and growth-associated gene expression","volume":"205","author":"Geremia","year":"2007","journal-title":"Exp. Neurol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1002\/nau.22264","article-title":"Neurotrophin therapy improves recovery of the neuromuscular continence mechanism following simulated birth injury in rats","volume":"32","author":"Gill","year":"","journal-title":"Neurourol. Urodyn."},{"key":"B18","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.juro.2013.01.082","article-title":"Stress incontinence in the era of regenerative medicine: reviewing the importance of the pudendal nerve","volume":"190","author":"Gill","year":"","journal-title":"J. Urol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1111\/j.1745-7599.2004.tb00441.x","article-title":"Stress urinary incontinence in women","volume":"16","author":"Gray","year":"2004","journal-title":"J. Am. Acad. Nurse Pract."},{"key":"B20","doi-asserted-by":"publisher","first-page":"F1047","DOI":"10.1152\/ajprenal.00173.2019","article-title":"Multiple doses of stem cells maintain urethral function in a model of neuromuscular injury resulting in stress urinary incontinence","volume":"317","author":"Janssen","year":"2019","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"F239","DOI":"10.1152\/ajprenal.00235.2012","article-title":"Effects of acute selective pudendal nerve electrical stimulation after simulated childbirth injury","volume":"304","author":"Jiang","year":"2013","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1002\/nau.20632","article-title":"Dual simulated childbirth injuries result in slowed recovery of pudendal nerve and urethral function","volume":"28","author":"Jiang","year":"","journal-title":"Neurourol. Urodyn."},{"key":"B22","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1016\/j.expneurol.2008.10.024","article-title":"Electrophysiological function during voiding after simulated childbirth injuries","volume":"215","author":"Jiang","year":"","journal-title":"Exp. Neurol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/j.brainres.2011.01.094","article-title":"Quantification of neurological and other contributors to continence in female rats","volume":"1382","author":"Jiang","year":"2011","journal-title":"Brain Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"F1555","DOI":"10.1152\/ajprenal.00431.2017","article-title":"Electrical stimulation of the pudendal nerve promotes neuroregeneration and functional recovery from stress urinary incontinence in a rat model","volume":"315","author":"Jiang","year":"2018","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e488","DOI":"10.1016\/j.wneu.2018.11.192","article-title":"Trends and cost analysis of upper extremity nerve injury using the national (nationwide) inpatient sample","volume":"123","author":"Karsy","year":"2019","journal-title":"World Neurosurg."},{"key":"B27","doi-asserted-by":"publisher","first-page":"4153","DOI":"10.1038\/s41598-017-03592-1","article-title":"Mesenchymal stem cells secretome-induced axonal outgrowth is mediated by BDNF","volume":"7","author":"Martins","year":"2017","journal-title":"Sci. Rep."},{"key":"B28","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1159\/000272115","article-title":"Birth trauma: its effect on the urine continence mechanisms","volume":"33","author":"Meyer","year":"1993","journal-title":"Gynakol. Geburtshilfliche Rundsch."},{"key":"B29","doi-asserted-by":"publisher","first-page":"2734","DOI":"10.1002\/stem.169","article-title":"Mesenchymal stem cells promote matrix metalloproteinase secretion by cardiac fibroblasts and reduce cardiac ventricular fibrosis after myocardial infarction","volume":"27","author":"Mias","year":"2009","journal-title":"Stem Cells"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1007\/s00192-017-3281-z","article-title":"An observational follow-up study on pelvic floor disorders to 3-5 years after delivery","volume":"28","author":"Ng","year":"2017","journal-title":"Int. Urogynecol. J."},{"key":"B31","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1097\/00005373-199807000-00025","article-title":"Analysis of upper and lower extremity peripheral nerve injuries in a population of patients with multiple injuries","volume":"45","author":"Noble","year":"1998","journal-title":"J. Trauma"},{"key":"B32","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.scr.2011.01.004","article-title":"Serum-deprived human multipotent mesenchymal stromal cells (MSCs) are highly angiogenic","volume":"6","author":"Oskowitz","year":"2011","journal-title":"Stem Cell Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"F277","DOI":"10.1152\/ajprenal.90602.2008","article-title":"Dual simulated childbirth injury delays anatomic recovery","volume":"296","author":"Pan","year":"2009","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1097\/MOT.0b013e32835a5aad","article-title":"Are stem cells the teacher or the student?","volume":"17","author":"Penn","year":"2012","journal-title":"Curr. Opin. Organ Transplant."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.1007\/s10529-012-0935-2","article-title":"Proteomic analysis of the impact of static culturing on the expansion of rat bone marrow mesenchymal stem cells","volume":"34","author":"Peter","year":"2012","journal-title":"Biotechnol. Lett."},{"key":"B36","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.1186\/1742-4755-11-S1-S3","article-title":"Essential childbirth and postnatal interventions for improved maternal and neonatal health","volume":"11","author":"Salam","year":"2014","journal-title":"Reprod. Health"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1136\/jnnp.47.12.1269","article-title":"Damage to the innervation of the voluntary anal and periurethral sphincter musculature in incontinence: an electrophysiological study","volume":"47","author":"Snooks","year":"1984","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"B38","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1007\/BF01648831","article-title":"Risk factors in childbirth causing damage to the pelvic floor innervation","volume":"1","author":"Snooks","year":"1986","journal-title":"Int. J. Colorectal Dis."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1358","DOI":"10.1002\/bjs.1800771213","article-title":"Effect of vaginal delivery on the pelvic floor: a 5-year follow-up","volume":"77","author":"Snooks","year":"1990","journal-title":"Br. J. Surg."},{"key":"B40","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1002\/9780470513941.ch9","article-title":"The neurogenic hypothesis of stress incontinence","volume":"151","author":"Swash","year":"1990","journal-title":"Ciba Found. Symp."},{"key":"B41","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1097\/PHM.0b013e31815e6370","article-title":"The incidence of peripheral nerve injury in extremity trauma","volume":"87","author":"Taylor","year":"2008","journal-title":"Am. J. Phys. Med. Rehabil."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.addr.2014.10.007","article-title":"Stem cells as drug delivery methods: application of stem cell secretome for regeneration","author":"Tran","year":"2015","journal-title":"Adv. Drug Deliv. Rev."},{"key":"B43","doi-asserted-by":"publisher","first-page":"3197","DOI":"10.1096\/fj.06-6558com","article-title":"SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction","volume":"21","author":"Zhang","year":"2007","journal-title":"FASEB J."}],"container-title":["Frontiers in Cellular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2022.866094\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T04:46:15Z","timestamp":1652849175000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2022.866094\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,18]]},"references-count":43,"alternative-id":["10.3389\/fncel.2022.866094"],"URL":"https:\/\/doi.org\/10.3389\/fncel.2022.866094","relation":{},"ISSN":["1662-5102"],"issn-type":[{"value":"1662-5102","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,18]]},"article-number":"866094"}}