The Dose-Effect Safety Profile of Skeletal Muscle Precursor Cell Therapy in a Dog Model of Intrinsic Urinary Sphincter Deficiency

Abstract

Locally injected skeletal muscle precursor cells (skMPCs) integrate into and restore the muscle layers, innervation, vasculature, and function of the sphincter complex in animal models of intrinsic urinary sphincter deficiency (ISD). The goal of the present study was to test the dose-effect safety profile of skMPC therapy in a dog model of ISD. Sphincter deficiency was created in 20 adult female dogs by surgically removing the skeletal muscle layer of the urinary sphincter complex. skMPCs isolated from the hind leg were expanded in culture and injected 4 weeks later into the sphincter complex at a dose of 25 million cells (n = 5), 50 million cells (n = 5), or 100 million cells (n = 5) per milliliter in a 2-ml volume. Five dogs received no sphincter injection. The measures of maximal sphincter pressure, complete blood count, and blood chemistry were performed monthly until their sacrifice at 9 months. At that point, full necropsy was performed to assess the safety of the skMPC injections. Injection of different doses of cells had no effects on the body weight, blood cell count, or kidney or liver function test results (p > .05 among the skMPC doses). Some incidental pathologic features were found in the lower urinary tract in all groups and were most likely associated with repeat catheterization. The maximal urinary sphincter pressure was higher in the 50 million cells per milliliter treatment group than in the other experimental groups (p < .05). The findings of the present study have confirmed that urinary sphincter injection of skMPCs results in no significant local or systemic pathologic features within the dose range that improves sphincter pressures. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:286-294

Precise injection of human mesenchymal stromal cells in the urethral sphincter complex of Göttingen minipigs without unspecific bulking effects

“…Therefore, studies employing large animal models complementing the experiments performed with rodents are important to investigate the therapeutic potential of cells under anatomically more relevant conditions. Some animal studies employed dogs to generate incontinence and to inject cells, others established incontinence in pigs and investigated cellular regeneration in this model . Urinary leak point pressure or urethral pressure profiles can be determined in these large animal models using standard clinical instruments.…”

“…Besides other aspects such as type of cell and amount of cells applied, 28,30,31,36 the length of the injection needle is important for the clinical outcome of SUI treatment. In a small clinical trial (eight patients, 1 year follow-up) patients treated with an 8 mm needle failed to present with a measurable benefit, whereas patients treated with a 10 mm needle reported improvement.…”

The Anatomy of Caprine Female Urethra and Characteristics of Muscle and Bone Marrow Derived Caprine Cells for Autologous Cell Therapy Testing

“…The proposed isolation protocol and culture conditions resulted in obtaining repeatable yield of 40–50 × 10(6) MDC after 3 weeks of culture. This is a cell number sufficient for intraurethral transplantation in an animal weighting about 40–50 kg according to previously published data (Williams et al, ). The population doubling time of caprine MDC presented herein amounted 40 hr what was higher than reported in pigs (23 or 26 hr depending on muscle type (Zhu et al, 2013)).…”

Ureteral ectopia and urethral sphincter mechanism incompetence: an update on diagnosis and management options

“…Perhaps a fresh approach is required? Alternatively, if we continue to look to human medicine for answers, the next advance in treatment seems likely to involve cell therapy to restore functional muscle within the urethra (Williams et al 2015).…”