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Stromal derived factor-1 plasmid as a novel injection for treatment of stress urinary incontinence in a rat model

  • Ahmad O. Khalifa
  • Michael Kavran
  • Amr Mahran
  • Ilaha Isali
  • Juliana Woda
  • Chris A. Flask
  • Marc S. Penn
  • Adonis K. HijazEmail author
Original Article

Abstract

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).

Methods

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.

Results

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.

Conclusions

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.

Keywords

Urinary incontinence Parturition Chemokine CXCL12 Plasmids 

Abbreviations

CXCL12

CXC motif chemokine 12

IP

intraperitoneal

IACUC

institutional animal care and use committee

IQR

interquartile range

SLPP

leak point pressure

MSCs

mesenchymal stem cells

PBS

phosphate-buffered saline

pSDF-1

plasmid of SDF-1

SDF-1

stromal-derived factor-1

skMPC

skeletal muscle precursor cell

SUI

stress urinary incontinence

VD

vaginal distention

Notes

Funding

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.

References

  1. 1.
    Cheater FM, Castleden CM. Epidemiology and classification of urinary incontinence. Baillieres Best Pract Res Clin Obstet Gynaecol. 2000;14(2):183–205.CrossRefPubMedGoogle Scholar
  2. 2.
    Ilie CP, Chancellor MB. Female urology-future and present. Rev Urol. 2010;12(2-3):e154–6.PubMedGoogle Scholar
  3. 3.
    Chapin K, Khalifa A, Mbimba T, McClellan P, Anderson J, Novitsky Y, et al. In vivo biocompatibility and time-dependent changes in mechanical properties of woven collagen meshes: a comparison to xenograft and synthetic mid-urethral sling materials. J Biomed Mater Res B Appl Biomater. 2018.  https://doi.org/10.1002/jbm.b.34138.
  4. 4.
    Chapple CR, Cruz F, Deffieux X, Milani AL, Arlandis S, Artibani W, et al. Consensus statement of the European Urology Association and the European Urogynaecological Association on the use of implanted materials for treating pelvic organ prolapse and stress urinary incontinence. Eur Urol. 2017;72(3):424–31.  https://doi.org/10.1016/j.eururo.2017.03.048.CrossRefPubMedGoogle Scholar
  5. 5.
    Robinson D, Castro-Diaz D, Giarenis I, Toozs-Hobson P, Anding R, Burton C, et al. What is the best surgical intervention for stress urinary incontinence in the very young and very old? An international consultation on incontinence research society update. Int Urogynecol J. 2015;26(11):1599–604.  https://doi.org/10.1007/s00192-015-2783-9.CrossRefPubMedGoogle Scholar
  6. 6.
    Kirchin V, Page T, Keegan PE, Atiemo KO, Cody JD, McClinton S, et al. Urethral injection therapy for urinary incontinence in women. Cochrane Database Syst Rev. 2017;7:Cd003881.  https://doi.org/10.1002/14651858.CD003881.pub4.PubMedGoogle Scholar
  7. 7.
    Hart ML, Izeta A, Herrera-Imbroda B, Amend B, Brinchmann JE. Cell therapy for stress urinary incontinence. Tissue Eng B Rev. 2015;21(4):365–76.  https://doi.org/10.1089/ten.TEB.2014.0627.CrossRefGoogle Scholar
  8. 8.
    Peters KM, Dmochowski RR, Carr LK, Robert M, Kaufman MR, Sirls LT, et al. Autologous muscle derived cells for treatment of stress urinary incontinence in women. J Urol. 2014;192(2):469–76.  https://doi.org/10.1016/j.juro.2014.02.047.CrossRefPubMedGoogle Scholar
  9. 9.
    Tran C, Damaser MS. Stem cells as drug delivery methods: application of stem cell secretome for regeneration. Adv Drug Deliv Rev. 2015;82-83:1–11.  https://doi.org/10.1016/j.addr.2014.10.007.CrossRefPubMedGoogle Scholar
  10. 10.
    Luo Q, Zhang B, Kuang D, Song G. Role of stromal-derived factor-1 in mesenchymal stem cell paracrine-mediated tissue repair. Curr Stem Cell Res Ther. 2016;11(7):585–92.CrossRefPubMedGoogle Scholar
  11. 11.
    Lau TT, Wang DA. Stromal cell-derived factor-1 (SDF-1): homing factor for engineered regenerative medicine. Expert Opin Biol Ther. 2011;11(2):189–97.  https://doi.org/10.1517/14712598.2011.546338.CrossRefPubMedGoogle Scholar
  12. 12.
    Sundararaman S, Miller TJ, Pastore JM, Kiedrowski M, Aras R, Penn MS. Plasmid-based transient human stromal cell-derived factor-1 gene transfer improves cardiac function in chronic heart failure. Gene Ther. 2011;18(9):867–73.  https://doi.org/10.1038/gt.2011.18.CrossRefPubMedGoogle Scholar
  13. 13.
    Penn MS, Mendelsohn FO, Schaer GL, Sherman W, Farr M, Pastore J, et al. An open-label dose escalation study to evaluate the safety of administration of nonviral stromal cell-derived factor-1 plasmid to treat symptomatic ischemic heart failure. Circ Res. 2013;112(5):816–25.  https://doi.org/10.1161/circresaha.111.300440.CrossRefPubMedGoogle Scholar
  14. 14.
    Boncher N, Vricella G, Kavran M, Xiao N, Hijaz A. Setting a new standard: updating the vaginal distention translational model for stress urinary incontinence. Neurourol Urodyn. 2012;31(1):190–4.  https://doi.org/10.1002/nau.21168.CrossRefPubMedGoogle Scholar
  15. 15.
    Wood HM, Kuang M, Woo L, Hijaz A, Butler RS, Penn M, et al. Cytokine expression after vaginal distention of different durations in virgin Sprague-Dawley rats. J Urol. 2008;180(2):753–9.  https://doi.org/10.1016/j.juro.2008.03.182.CrossRefPubMedGoogle Scholar
  16. 16.
    Sadeghi Z, Isariyawongse J, Kavran M, Izgi K, Marini G, Molter J, et al. Mesenchymal stem cell therapy in a rat model of birth-trauma injury: functional improvements and biodistribution. Int Urogynecol J. 2015.  https://doi.org/10.1007/s00192-015-2831-5.
  17. 17.
    Penn MS, Pastore J, Miller T, Aras R. SDF-1 in myocardial repair. Gene Ther. 2012;19:583.  https://doi.org/10.1038/gt.2012.32.CrossRefPubMedGoogle Scholar
  18. 18.
    Abruzzese RV, Godin D, Burcin M, Mehta V, French M, Li Y, et al. Ligand-dependent regulation of plasmid-based transgene expression in vivo. Hum Gene Ther. 1999;10(9):1499–507.  https://doi.org/10.1089/10430349950017833.CrossRefPubMedGoogle Scholar
  19. 19.
    Williams JK, Dean A, Badra S, Lankford S, Poppante K, Badlani G, et al. Cell versus chemokine therapy in a nonhuman primate model of chronic intrinsic urinary sphincter deficiency. J Urol. 2016;196(6):1809–15.  https://doi.org/10.1016/j.juro.2016.05.106.CrossRefPubMedGoogle Scholar
  20. 20.
    Koudy Williams J, Dean A, Lankford S, Andersson KE. Efficacy and initial safety profile of CXCL12 treatment in a rodent model of urinary sphincter deficiency. Stem Cells Transl Med. 2017;6(8):1740–6.  https://doi.org/10.1002/sctm.16-0497.CrossRefPubMedGoogle Scholar
  21. 21.
    Altman D, Ekstrom A, Gustafsson C, Lopez A, Falconer C, Zetterstrom J. Risk of urinary incontinence after childbirth: a 10-year prospective cohort study. Obstet Gynecol. 2006;108(4):873–8.  https://doi.org/10.1097/01.AOG.0000233172.96153.ad.CrossRefPubMedGoogle Scholar
  22. 22.
    Johannessen HH, Stafne SN, Falk RS, Stordahl A, Wibe A, Morkved S. Prevalence and predictors of double incontinence 1 year after first delivery. Int Urogynecol J. 2018.  https://doi.org/10.1007/s00192-018-3577-7.
  23. 23.
    Woo LL, Hijaz A, Kuang M, Penn MS, Damaser MS, Rackley RR. Over expression of stem cell homing cytokines in urogenital organs following vaginal distention. J Urol. 2007;177(4):1568–72.  https://doi.org/10.1016/j.juro.2006.11.047.CrossRefPubMedGoogle Scholar
  24. 24.
    Kaplani K, Koutsi S, Armenis V, Skondra FG, Karantzelis N, Tsaniras SC, et al. Wound healing related agents: ongoing research and perspectives. Adv Drug Deliv Rev. 2018.  https://doi.org/10.1016/j.addr.2018.02.007.
  25. 25.
    Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017;45(D1):D353–d361.  https://doi.org/10.1093/nar/gkw1092.CrossRefPubMedGoogle Scholar
  26. 26.
    Palacios JL, Juarez M, Moran C, Xelhuantzi N, Damaser MS, Cruz Y. Neuroanatomic and behavioral correlates of urinary dysfunction induced by vaginal distension in rats. Am J Physiol Ren Physiol. 2016;310(10):F1065–73.  https://doi.org/10.1152/ajprenal.00417.2015.CrossRefGoogle Scholar
  27. 27.
    Glass DJ. Molecular mechanisms modulating muscle mass. Trends Mol Med. 2003;9(8):344–50.CrossRefPubMedGoogle Scholar
  28. 28.
    Zhang PZ, Cao XS, Jiang XW, Wang J, Liang PF, Wang SJ, et al. Acoustical stimulus changes the expression of stromal cell-derived factor-1 in the spiral ganglion neurons of the rat cochlea. Neurosci Lett. 2014;561:140–5.  https://doi.org/10.1016/j.neulet.2013.12.061.CrossRefPubMedGoogle Scholar
  29. 29.
    Viktrup L, Rortveit G, Lose G. Risk of stress urinary incontinence twelve years after the first pregnancy and delivery. Obstet Gynecol. 2006;108(2):248–54.  https://doi.org/10.1097/01.AOG.0000226860.01127.0e.CrossRefPubMedGoogle Scholar
  30. 30.
    Chung ES, Miller L, Patel AN, Anderson RD, Mendelsohn FO, Traverse J, et al. Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: the STOP-HF randomized phase II trial. Eur Heart J. 2015;36(33):2228–38.  https://doi.org/10.1093/eurheartj/ehv254.CrossRefPubMedGoogle Scholar

Copyright information

© The International Urogynecological Association 2019

Authors and Affiliations

  • Ahmad O. Khalifa
    • 1
    • 2
  • Michael Kavran
    • 1
  • Amr Mahran
    • 1
  • Ilaha Isali
    • 1
  • Juliana Woda
    • 3
  • Chris A. Flask
    • 4
    • 5
    • 6
  • Marc S. Penn
    • 7
  • Adonis K. Hijaz
    • 1
    Email author
  1. 1.Department of Urology, University Hospitals Cleveland Medical CenterCase Western Reserve UniversityClevelandUSA
  2. 2.Department of UrologyMenoufia UniversityShibin El KomEgypt
  3. 3.Juventus TherapeuticsClevelandUSA
  4. 4.Departments of RadiologyCase Western Reserve UniversityClevelandUSA
  5. 5.Departments of Biomedical EngineeringCase Western Reserve UniversityClevelandUSA
  6. 6.Departments of PediatricsCase Western Reserve UniversityClevelandUSA
  7. 7.Summa Health Heart and Vascular InstituteAkronUSA

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