Cell therapy by mesenchymal stromal cells versus myoblasts in a pig model of urinary incontinence

The leading cause of stress urinary incontinence in women is the urethral sphincter muscle deficiency caused by mechanical stress during pregnancy and vaginal delivery. In men, prostate cancer surgery and injury of local nerves and muscles are associated with incontinence. Current treatment often fails to satisfy the patient's needs. Cell therapy may improve the situation. We therefore investigated the regeneration potential of cells in ameliorating sphincter muscle deficiency and urinary incontinence in a large animal model. Urethral sphincter deficiency was induced surgically in gilts by electrocautery and balloon dilatation. Adipose tissue-derived stromal cells and myoblasts from Musculus semitendinosus were isolated from male littermates, expanded, characterized in depth for expression of marker genes and in vitro differentiation, and labelled. The cells were injected into the deficient sphincter complex of the incontinent female littermates. Incontinent gilts receiving no cell therapy served as controls. Sphincter deficiency and functional regeneration were recorded by monitoring the urethral wall pressure during follow-up by two independent methods. Cells injected were detected in vivo during follow-up by transurethral fluorimetry, ex vivo by fluorescence imaging, and in cryosections of tissues targeted by immunofluorescence and by PCR of the SRY gene. Partial spontaneous regeneration of sphincter muscle function was recorded in control gilts, but the sphincter function remained significantly below levels measured prior to induction of incontinence (67.03±14.00%, n=6, p<0.05). Injection of myoblasts yielded an improved sphincter regeneration within five weeks of follow-up but did not reach significance compared to control gilts (81.54±25.40%, n=5). A significant and full recovery of the urethral sphincter function was observed upon injection of adipose tissue-derived mesenchymal stromal cells within five weeks of follow-up (100.4±23.13%, n=6, p<0.05). Injection of stromal cells provoked slightly stronger infiltration of CD45pos leukocytes compared to myoblasts injections and controls. The data of this exploratory study indicate that adipose tissue-derived mesenchymal stromal cells inherit a significant potential to regenerate the function of the urethral sphincter muscle.