Local versus intravenous injections of skeletal muscle precursor cells in nonhuman primates with acute or chronic intrinsic urinary sphincter deficiency

Abstract

BackgroundMany factors may influence the efficacy of cell therapy for intrinsic urinary sphincter deficiency (ISD), including the route of administration of the cells and the condition of the sphincter. The goal of this study was to compare local versus intravenous administration of autologous skeletal muscle precursor cells (skMPCs) when administered to nonhuman primates (NHPs) with either acute or chronic ISD.MethodsThirty-two adult female monkeys were divided into eight groups (n = 4/group): (1) control; (2) surgically induced ISD/no treatment; (3) acute ISD (6-week duration)/local vehicle only; (4) acute ISD/local skMPC injection; (5) acute ISD/systemic skMPC; (6) chronic ISD (6-month duration)/local vehicle; (7) chronic ISD/local skMPC; (8) chronic ISD/systemic skMPC. Maximal urethral pressures (MUP) were measured prior to ISD, prior to treatment and at 3 and 6 months following treatment. Quantitative histology was used to measure muscle/collagen content, somatic innervation, and vascularity of the sphincter complexes.ResultsIn NHPs with acute ISD both systemic and local administration of skMPCs increased resting MUP values and sphincter muscle content (p < 0.05 vs. ISD/vehicle). However, the effects of systemic skMPC administration were significantly lower than those of local injection (p > 0.05). In NHPs with chronic ISD local skMPC administration had reduced (compared to NHPs with acute ISD) effects on MUP and sphincter muscle values (p < 0.05 vs. acute ISD/skMPC); systemic administration had no effect. Pudendal nerve-stimulated increases in MUP were significant only in acute ISD NHPs with local skMPC treatment (p < 0.05 vs. resting MUP). The extent of sphincter vascularization and innervation were directly related to MUP and sphincter muscle content.ConclusionsBoth the chronicity of ISD and the route of cell injection influence the efficacy of cell therapy in monkey models of ISD. This may be related to the relative ability of cells to stimulate vascularization and re-innervation in these different treatment conditions.

Determinates of muscle precursor cell therapy efficacy in a nonhuman primate model of intrinsic urinary sphincter deficiency

“…The rationale for these subgroup analyses was that these factors (age, body weight and social stress have been shown to influence the risk of diseases and been shown to influence, directly or indirectly the efficacy of cell therapies [8–12]. The major finding of this study was that the efficacy of skMPC therapy was reduced in older monkeys, in heavier monkeys and in monkeys with psychosocial stress – associated with reduced endogenous estrogen production.…”

“…We recently reported reduced efficacy of skMPCs in nonhuman primates (NHPs) with chronic (versus acute) intrinsic urinary sphincter deficiency (ISD) [8]. Senescence of stem cells, associated with aging is reported to dramatically reduce the effects of muscle regeneration and the efficacy of muscle cell therapy [9].…”

Stem cell in urology—are we at the cusp of a new era?

“…Assuming that mechanical injury/ dysfunction due to menopause or childbirth to be an important component of SUI, various investigators have injected bone marrow derived, mesenchymal or human amniotic fluid derived stem cells into the sphincter with varying results ( 7 ). A preclinical study has shown that both the chronicity of the intrinsic sphincter deficiency and the route of injection of stem cells (local vs. intravenous) affect the outcome with local injection being more effective ( 8 ). A randomized clinical trial published in 2007 ( 9 ) compared periurethral injections of autologous myoblasts and fibroblasts with conventional collagen in females with stress incontinence.…”

Nonhuman primate model of persistent erectile and urinary dysfunction following radical prostatectomy: Feasibility of minimally invasive therapy

“…Cynomolgus monkeys share with human beings a similar genitourinary anatomy and physiology, including the risk for age associated diseases . We have been able to produce chronic urinary sphincter dysfunction (ISD) in females of this species and successfully treat them with the chemokine CXCL12, which is a chemotactic factor for mesenchymal stem cells and plays an important role in angiogenesis . This finding provided the rationale for testing CXCL12 in a monkey model of post‐radical prostatectomy incontinence and erectile dysfunction.…”