Abstract

Urinary incontinence, defined as the complaint of any involuntary loss of urine, is a pathological condition, which affects 30% females and 15% males over 60, often following a progressive decrease of rhabdosphincter cells due to increasing age or secondary to damage to the pelvic floor musculature, connective tissue and/or nerves. Recently, stem cell therapy has been proposed as a source for cell replacement and for trophic support to the sphincter. To develop new therapeutic strategies for urinary incontinence, we studied the interaction between mesenchymal stem cells (MSCs) and muscle cells in vitro; thereafter, aiming at a clinical usage, we analyzed the supporting role of MSCs for muscle cells in vitro and in in vivo xenotransplantation. MSCs can express markers of the myogenic cell lineages and give rise, under specific cell culture conditions, to myotube-like structures. Nevertheless, we failed to obtain mixed myotubes both in vitro and in vivo. For in vivo transplantation, we tested a new protocol to collect human MSCs from whole bone marrow, to get larger numbers of cells. MSCs, when transplanted into the pelvic muscles close to the external urethral sphincter, survived for a long time in absence of immunosuppression, and migrated into the muscle among fibers, and towards neuromuscular endplates. Moreover, they showed low levels of cycling cells, and did not infiltrate blood vessels. We never observed formation of cell masses suggestive of tumorigenesis. Those which remained close to the injection site showed an immature phenotype, whereas those in the muscle had more elongated morphologies. Therefore, MSCs are safe and can be easily transplanted without risk of side effects in the pelvic muscles. Further studies are needed to elucidate their integration into muscle fibers, and to promote their muscular transdifferentiation either before or after transplantation.

Highlights

  • Urinary incontinence (UI), defined as the complaint of any involuntary loss of urine, represents an increasingly frequent pathological condition, which occurs in 30% females and 15% males aged over 60

  • Bulbocavernosus and ischiocavernosus muscles appeared as striated structures in which transplanted cells occupied a peripheral position, suggesting that bone marrow (BM)-hMSCs can survive for long periods within muscular tissue, no colocalization of markers was found, we could not hypothesize any fusion between BM-hMSCs and striated muscle (Fig. 6A). a-BTX staining was diffuse one month after transplantation, whereas 4 months later we found that several BM-hMSCs were located close to acetylcholine receptors (Ach-Rs) (Fig. 6B)

  • Cell Therapy Products (CTP) are medicinal products for treating or preventing disease in human beings and their manufacturing process have to comply with the principles and guidelines of GMP for medicinal products for human use

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Summary

Introduction

Urinary incontinence (UI), defined as the complaint of any involuntary loss of urine, represents an increasingly frequent pathological condition, which occurs in 30% females and 15% males aged over 60. An important cause of SUI is a progressive decrease of rhabdosphincter cells due to increasing age, which is caused by physiological apoptosis [2]. The significant progressive decrease in the number of striated muscle cells in the rabdosphincter with ageing represents a pathogenetic hypothesis for the high incidence of incontinence. Pharmacology failed to treat the disease: for instance, alpha agonists had no significant effect on the incontinence [3]. Non-invasive treatment is likely to be offered in mild cases and may entail pelvic floor muscle re-education

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