Mesenchymal stem cell therapy in a rat model of birth-trauma injury: functional improvements and biodistribution.
OBJECTIVE
We evaluated the potential role of human mesenchymal stem cells (hMSCs) in improvement of urinary continence following birth-trauma injury.


METHODS
Human MSCs were injected periurethrally or systemically into rats immediately after vaginal distention (VD) (n = 90). Control groups were non-VD (uninjured/untreated, n = 15), local or systemic saline (injection/control, n = 90), and dermofibroblast (cell therapy/control, n = 90). Leak-point pressure (LPP) was measured 4, 10, and 14 days later. Urethras were morphometrically evaluated. In another sets of VD and non-VD rats, the fate of periurethrally injected hMSC, biodistribution, and in vivo viability was studied using human Alu genomic repeat staining, PKH26 labeling, and luciferase-expression labeling, respectively.


RESULTS
Saline- and dermofibroblast-treated control rats demonstrated lower LPP than non-VD controls at days 4 and 14 (P < 0.01). LPP after systemic hMSC and periurethral hMSC treatment were comparable with non-VD controls at 4, 10, and 14 days (P > 0.05). Local saline controls demonstrated extensive urethral tissue bleeding. The connective tissue area/urethral section area proportion and vascular density were higher in the local hMSC- versus the saline-treated group at 4 and 14 days, respectively. No positive Alu-stained nuclei were observed in urethras at 4, 10, and 14 days. PKH26-labelled cells were found in all urethras at 2 and 24 h. Bioluminescence study showed increased luciferase expression from day 0 to 1 following hMSC injection.


CONCLUSIONS
Human MSCs restored the continence mechanism with an immediate and sustained effect in the VD model, while saline and dermofibroblast therapy did not. Human MSCs remained at the site of periurethral injection for <7 days. We hypothesize that periurethral hMSC treatment improves vascular, connective tissue, and hemorrhage status of urethral tissues after acute VD injury.
Urology Institute, University Hospitals of Case Medical Center, Department of Urology, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH, 44106, USA.|Department of Urology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Zhina
Z
Sadeghi
Urology Institute, University Hospitals of Case Medical Center, Department of Urology, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH, 44106, USA.|Department of Urology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Justin
J
Isariyawongse
Department of Urology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Michael
M
Kavran
Department of Urology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Kenan
K
Izgi
Department of Urology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.|Laboratory of Experimental Research on Gynecology and Obstetrics, Department of Gynecology and Obstetrics, Botucatu Medical School, Botucatu, Brazil.
Gabriela
G
Marini
Department of Radiology, Case Western Reserve University, Cleveland, OH, USA.
Joseph
J
Molter
Department of Urology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Firouz
F
Daneshgari
Department of Radiology, Case Western Reserve University, Cleveland, OH, USA.|Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA.|Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA.
Chris A
CA
Flask
Skeletal Research Center, Biology Department, Case Western Reserve University, Cleveland, OH, USA.
Arnold
A
Caplan
Urology Institute, University Hospitals of Case Medical Center, Department of Urology, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH, 44106, USA. Adonis.Hijaz@UHhospitals.org.|Department of Urology, Case Western Reserve University School of Medicine, Cleveland, OH, USA. Adonis.Hijaz@UHhospitals.org.
Adonis
A
Hijaz
D000818:Animals; D058948:Cell Tracking; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology; D036801:Parturition; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D014521:Urethra / Q000293:injuries / Q000473:pathology*; D014549:Urinary Incontinence / Q000209:etiology / Q000503:physiopathology* / Q000628:therapy*
Birth-trauma injury; MSC biodistribution; Mesenchymal stem cell; Stem cell fate; Stress urinary incontinence