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

Abstract

BackgroundCell therapy for intrinsic urinary sphincter deficiency (ISD) in women has been moderately effective, and improvements are needed. To improve treatment efficacy, it is important to better understand determinates of cell efficacy in the different patient cohorts. We have reported that in nonhuman primates the chronicity of ISD may affect cell efficacy, but additional factors (age, psychosocial stress, hormone status, body weight) can be associated with many disease/treatment outcomes in women – and these factors are the focus of this study.MethodsAdult female cynomolgus monkeys were divided into groups: (1) younger (n = 10, 5–8 years of age) versus older (n = 10, 13–18 years of age); (2) age-matched/socially subordinate (n = 15) versus socially dominant (n = 15); and (3) age-matched lower body weight (n = 6) versus higher body weight (n = 6). Autologous skeletal muscle precursor cells (skMPCs, 5 million) were injected into the urinary sphincter 6 weeks after a surgically induced ISD procedure. Resting and pudendal nerve-stimulated maximal urethral pressures (MUP) were measured before, and 3 and 6 months post-skMPC treatment and urinary sphincter muscle/collagen content within the sphincter complex was measured by quantitative histology 6 months posttreatment.ResultsEfficacy of skMPCs on MUP and sphincter muscle/collagen ratios are affected by age (average 40% reduction in efficacy, p < 0.05 vs. younger NHPs), social stress (average 30% reduction in efficacy, p < 0.05 vs. socially dominant) and body weight/fasting glucose concentrations (average 35% reduction in efficacy, p < 0.05 vs. lower body weight).ConclusionMultiple factors (age, stress-induced dysmenorrhea, and body weight) affect the efficacy of cell therapy to restore structure and function in the urinary sphincter complex in NHPs with ISD. Consideration of, and alternatives for, these patient cohorts should be considered.

Preparing the Bone Tissue Regeneration Ground by Exosomes: From Diagnosis to Therapy

“…For example, one group reported that the therapeutic effect of MSC-exosomes in an OA animal model is a result of exosomes enhancing synthesis and suppressing the degradation of the chondrocyte extracellular matrix (ECM). This was confirmed via an in vitro investigation on chondrocytes treated with the proinflammatory cytokine interleukin (IL)-1β, where exosomes increased collagen type II synthesis and decreased the expression of ADAMTS5, an ECM degrading enzyme [ 74 ]. A second study reported that MSC-exosomes protected OA mice from joint damage by inducing chondroprotective actions.…”

“…In which, inflammation within the synovial capsule causes a loss of articular cartilage which in turn leads to joint degeneration, and sclerotic changes to the surrounding bone tissue [ 72 ]. Studies have shown that MSC-exosomes induce healing by promoting chondrocytes proliferation and migration, which leads to cartilage regeneration and the protection of the underling bone tissue [ 73 ]. Another reported exosomal action that is crucial in OA management is restoring the synovial homeostasis, which is essential for tissue healing and repair.…”

Therapeutic Potential of Human Adipose-Derived Stem Cell Exosomes in Stress Urinary Incontinence – An in Vitro and in Vivo Study

“…Various approaches using cellular and biochemical components have been explored in vitro and in vivo to enhance the regenerative capacity of injured skeletal muscle and peripheral nerves. Among them, stem cell-based therapies have clear beneficial effects on skeletal muscle and peripheral nerve repair [32,33]. Although the mechanisms by which stem cell therapy act are still unknown, recent evidence has suggested they might be related to long-distance cell-to-cell communication via secreted paracrine factors in the extracellular environment [34].…”

An Injectable Hyaluronan–Methylcellulose (HAMC) Hydrogel Combined with Wharton’s Jelly-Derived Mesenchymal Stromal Cells (WJ-MSCs) Promotes Degenerative Disc Repair

“…Chronic low back pain (LBP) is the leading cause of disability worldwide and the social and economic impact is enormous [ 1 ]. Not all degenerated discs exhibit chronic LBP, however, intravertebral disc (IVD) degeneration is considered as a major cause of chronic LBP [ 1 , 2 , 3 , 4 ]. IVD degeneration is a complex and multifactorial process, influenced by genetic, nutritional, and mechanical factors [ 5 ].…”

“…These molecules can be produced by both IVD cells and immune cells, such as macrophages [ 6 ], and are known to be associated with discogenic back pain [ 6 ]. IVD degeneration is characterized by the loss of IVD cells and extracellular matrix (ECM) such as aggrecan and collagen type II, with the upregulation of matrix metalloproteinases (MMPs) and inflammatory mediators leading to progressive and irreversible damage of IVD structure [ 1 , 3 , 4 , 6 , 7 , 8 ]. Eventually, IVD degeneration can lead to the onset of additional spinal conditions, including disc herniation, spinal stenosis, facet joint osteoarthritis, and spondylolisthesis [ 1 , 3 , 9 , 10 ].…”