Abstract
BackgroundThe therapeutic effects of human embryonic stem cell-derived multipotent mesenchymal stem cells (M-MSCs) were evaluated for detrusor underactivity (DUA) in a rat model with atherosclerosis-induced chronic bladder ischemia (CBI) and associated mechanisms.MethodsSixteen-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 × 105 cells (250 K, 500 K, or 1000 K; 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.ResultsCBI 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 1000 K 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, leading to increased angiogenesis in the CBI bladder. 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.ConclusionsSingle 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.Graphical abstract
Highlights
Detrusor underactivity (DUA) is defined as “low detrusor pressure or short detrusor contraction time, usually in combination with a low urine flow rate resulting in prolonged bladder emptying and/or failure to achieve complete bladder emptying within a normal time span” by the international continence society standardization [1, 2]
mesenchymal stem cells (MSCs) can been isolated from adult or fetal tissues [5], or they can be derived from pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs) and induced PSCs [6,7,8]
We aimed to investigate the therapeutic effects of mesenchymal stem cells (M-MSCs) treatment in a detrusor underactivity (DUA) rat model with extensive vascular endothelial damage of the iliac arteries
Summary
Detrusor underactivity (DUA) is defined as “low detrusor pressure or short detrusor contraction time, usually in combination with a low urine flow rate resulting in prolonged bladder emptying and/or failure to achieve complete bladder emptying within a normal time span” by the international continence society standardization [1, 2]. The beneficial effects of MSC therapy include the generation of various preclinical bladder dysfunction models and reports of positive patient outcomes from clinical trials [9,10,11,12,13,14,15,16,17]. The therapeutic effects of human embryonic stem cell-derived multipotent mesenchymal stem cells (M-MSCs) were evaluated for detrusor underactivity (DUA) in a rat model with atherosclerosis-induced chronic bladder ischemia (CBI) and associated mechanisms. M-MSCs at a density of 2.5, 5.0, or 10.0 × 105 cells (250 K, 500 K, or 1000 K; 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). Histological analysis revealed that M-MSC therapy reduced CBI-induced injuries including bladder fibrosis, muscular loss, and apoptosis. Transcriptomes of the CBI-injured bladders were characterized by the complement system, inflammatory, and ion transportrelated pathways, which were restored by M-MSC therapy
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