To our best knowledge, animal models reproducing detrusor underactivity (DUA) are scarce. Previous studies suggested that atherosclerosis, a common aging-associated disorder, has a role in the pathogenesis of lower urinary tract dysfunction, such as DUA. We tried to develop a rat model of atherosclerosis-induced chronic bladder ischemia (CBI) and investigate the effect of chronic bladder ischemia on bladder function. Recently, as stem cell research presents new possibilities for treating previously intractable disorders, stem cell-based therapy has also been proposed as a novel therapeutic approach for incurable bladder disorders, including stress urinary incontinence, overactive bladder, detrusor underactivity, and bladder or urethral injury. Also, we reported beneficial outcomes of adult tissues derived mesenchymal stem cells (MSCs) for treating Chronic Bladder Ischemia rat model which is a chronic inflammatory condition of the bladder. However, direct assessment of the biological and molecular properties of engrafted cells in the pathological environment has not been performed for current MSC therapies. We tried to evaluate bladder function and pathological efficacy through stem cell therapy of chronic bladder ischemia rat model.

Sixteen-week-old male Sprague–Dawley rats were divided into five groups (n=10). The DUA groups underwent 30 bilateral repetitions of endothelial injury to the iliac arteries to induce CBI, while the sham control group underwent a sham operation. All rats used in this study received a 1.25% cholesterol diet for 8 weeks. M-MSCs at a density of 2.5, 5.0, or 10.0 x 105 cells (250K, 500K, or 1,000K; K = a thousand) were injected directly into the bladder 7 weeks post-injury, while the sham and DUA group were treated only with vehicle (phosphate buffer solution). One week after M-MSC injection, awake cystometry was performed on the rats. Then, the bladders were harvested, studied in an organ bath, and prepared for histological and gene expression analyses.

CBI by iliac artery injury reproduced voiding defects characteristic of DUA with decreased micturition pressure, increased micturition interval, and a larger residual volume. The pathological DUA properties were improved by M-MSC treatment in a dose-dependent manner, with the 1,000K group producing the best efficacy. Histological analysis revealed that M-MSC therapy reduced CBI-induced injuries including bladder fibrosis, muscular loss, and apoptosis. Transplanted M-MSCs mainly engrafted as vimentin and NG2 positive pericytes rather than myocytes. Transcriptomes of the CBI-injured bladders were characterized by the complement system, inflammatory, and ion transport-related pathways, which were restored by M-MSC therapy.

To our knowledge, this is the first demonstration of superior therapeutic efficacy, in vivo integration of hESC progeny for treating DUA model.

Single injection of M-MSCs directly into the bladder of a CBI-induced DUA rat model improved voiding profiles and repaired the bladder muscle atrophy in a dose-dependent manner.

Induction of detrusor underactivity by extensive vascular endothelial damages of iliac arteries in a rat model and its pathophysiology in the genetic levels_Scientific Reports (2019) 9:16328