Mesenchymal stem cells and their secretome partially restore nerve and urethral function in a dual muscle and nerve injury stress urinary incontinence model.
*Mesenchymal Stem Cell Transplantation; Animals; Conditioned; Culture Media; elastin; external urethral sphincter; Female; Injections; Intraperitoneal; Intravenous; Mesenchymal Stem Cells/metabolism; paracrine action; Parturition; pudendal nerve; Pudendal Nerve/injuries/*physiology; Rats; Sprague-Dawley; Stress/etiology/*prevention & control; Urethra/injuries/*physiology; urinary incontinence; Urinary Incontinence
Childbirth injures muscles and nerves responsible for urinary continence. Mesenchymal stem cells (MSCs) or their secretome given systemically could provide therapeutic benefit for this complex multisite injury. We investigated whether MSCs or their secretome, as collected from cell culture, facilitate recovery from simulated childbirth injury. Age-matched female Sprague-Dawley rats received pudendal nerve crush and vaginal distension (PNC+VD) and a single intravenous (iv) injection of 2 million MSCs or saline. Controls received sham injury and iv saline. Additional rats received PNC+VD and a single intraperitoneal (ip) injection of concentrated media conditioned by MSCs (CCM) or concentrated control media (CM). Controls received a sham injury and ip CM. Urethral and nerve function were assessed with leak point pressure (LPP) and pudendal nerve sensory branch potential (PNSBP) recordings 3 wk after injury. Urethral and pudendal nerve anatomy were assessed qualitatively by blinded investigators. Quantitative data were analyzed using one-way ANOVA and Holm-Sidak post hoc tests with P \textless 0.05 indicating significant differences. Both LPP and PNSBP were significantly decreased 3 wk after PNC+VD with saline or CM compared with sham-injured rats, but not with MSC or CCM. Elastic fiber density in the urethra increased and changed in orientation after PNC+VD, with a greater increase in elastic fibers with MSC or CCM. Pudendal nerve fascicles were less dense and irregularly shaped after PNC+VD and had reduced pathology with MSC or CCM. MSC and CCM provide similar protective effects after PNC+VD, suggesting that MSCs act via their secretions in this dual muscle and nerve injury.
Deng Kangli; Lin Dan Li; Hanzlicek Brett; Balog Brian; Penn Marc S; Kiedrowski Matthew J; Hu Zhiquan; Ye Zhangqun; Zhu Hui; Damaser Margot S
American journal of physiology. Renal physiology
2015
2015-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajprenal.00510.2014" target="_blank" rel="noreferrer noopener">10.1152/ajprenal.00510.2014</a>
Effect of Pregnancy and Delivery on Cytokine Expression in a Mouse Model of Pelvic Organ Prolapse.
Amino Acid Oxidoreductases/*genetics/metabolism; Animal; Animals; Chemokine CCL7/genetics/metabolism; Chemokine CXCL12/genetics/metabolism; Delivery; Female; Humans; Knockout; Mice; Models; Obstetric/*adverse effects/methods; Pelvic Organ Prolapse/*genetics/metabolism/pathology; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; Urethra/metabolism; Urinary Bladder/metabolism; Vagina/metabolism
OBJECTIVES: The aim of this study was to determine the effect of pregnancy and delivery mode on cytokine expression in the pelvic organs and serum of lysyl oxidase like-1 knockout (LOXL1 KO) mice, which develop pelvic organ prolapse after delivery. METHODS: Bladder, urethra, vagina, rectum, and blood were harvested from female LOXL1 KO mice during pregnancy, after vaginal or cesarean delivery, and from sham cesarean and unmanipulated controls. Pelvic organs and blood were also harvested from pregnant and vaginally delivered wild-type (WT) mice and from unmanipulated female virgin WT controls. Specimens were assessed using quantitative real-time reverse transcription polymerase chain reaction and/or enzyme-linked immunosorbent assay. RESULTS: Both CXCL12 and CCL7 mRNA were significantly up-regulated in the vagina, urethra, bladder, and rectum of pregnant LOXL1 KO mice compared with pregnant WT mice, suggesting systemic dysregulation of both of these cytokines in LOXL1 KO mice as a response to pregnancy.The differences in cytokine expression between LOXL1 KO and WT mice in pregnancy persisted after vaginal delivery. CCL7 gene expression increases faster and to a greater extent in LOXL1 KO mice, translating to longer lasting increases in CCL7 in serum of LOXL1 KO mice after vaginal delivery, compared with pregnant mice. CONCLUSIONS: Lysyl oxidase like-1 KO mice have an increased cytokine response to pregnancy perhaps because they are less able to reform and re-cross-link stretched elastin to accommodate pups, and this resultant tissue stretches during pregnancy. The up-regulation of CCL7 after delivery could provide an indicator of level of childbirth injury, to which the urethra and vagina seem to be particularly vulnerable.
Couri Bruna M; Lenis Andrew T; Borazjani Ali; Balog Brian M; Kuang Mei; Butler Robert S; Penn Marc S; Damaser Margot S
Female pelvic medicine & reconstructive surgery
2017
2017-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1097/SPV.0000000000000394" target="_blank" rel="noreferrer noopener">10.1097/SPV.0000000000000394</a>