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.

The arterial injury (AI) group underwent endothelial injury of the iliac arteries AI-30, 30 times and received a 1.25% cholesterol diet. The sham group underwent sham operation and received a 1.25% cholesterol diet. 7 weeks after endothelial injury, the submucosal layer of the anterior wall and dome of the bladder was injected with (250k, 500k, 1000k) human embryonic stem cell derived multipotent stem cells (M-MSCs) and with phosphate-buffer solution served as sham group. One week after M-MSC injection, cystometry were performed without anesthesia. Histological examination of the iliac arteries and the bladder was performed. The bladder was also processed for organ bath study.

Cystometry showed that the frequency of reflex bladder contractions and micturition pressure were significantly lower in the DUA group. However, it was confirmed that the micturition pressure increased with dose dependent after M-MSC treatment. Also, cystometry showed that in the 1000k group, micturition interval, micturition volume, and residual volume were decreased. Histo-pathophysiological study showed that Masson’s trichrome staining of bladder tissue revealed an decreased percent of collagen in the muscle layer in the 250k, 500k, and 1000k groups compared to the DUA group. Moreover, immunostaining with anti-alpha smooth muscle actin (α SMA) antibody revealed that the bladder muscle layer in the 250k, 500k, and 1000k groups was significantly increase than in the DUA group.

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

The bladder function of detrusor underactivity rat model improved after M-MSC treatment. In addition, the collagen of the muscle layer of the bladder was reduced, and the amount of bladder muscle was also increased.

Induction of detrusor underactivity by extensive vascular endothelial damages of iliac arteries in a rat model and its pathophysiology in the genetic levels
Improved efficacy and in vivo cellular properties of human embryonic stem cell derivative in a preclinical model of bladder pain syndrome