To investigate the therapeutic effects and fate of transplanted mesenchymal stem cells (MSCs) in streptozotocin (STZ)-induced diabetic cystopathy rat model. 
To identify the minimum therapeutic dosage of MSCs in STZ rat model and compare the efficacy with other type of stem cell.

Eight-week-old female Sprague Dawley rats were divided into five groups; sham (n=5), DM (n=5), DM+M-MSC 1,000K (n=5), DM+M-MSC 500K (n=5), DM+M-MSC 250K (n=5). After overnight fasting, STZ (50mg/kg) was injected intraperitoneally and rats with serum glucose ≥ 200mg/dL on day 3 were included. Three weeks later, different dosages of MSCs were directly injected into submucosal layer of bladder with 26 gauge needle. Changes in detrusor function and histology were evaluated one week after stem cell transplantation by awake cystometry, organ bath, immunohistochemical staining and gene expression analysis. Minimum therapeutic dosage was determined based on awake cystometry. Next, the efficacy of minimum MSCs was compared with umbilical cord-derived stem cells (UC-MSC) (n=5, respectively). Long-term therapeutic effect was assessed two weeks and four weeks (n=5, respectively) after stem cell injection by awake cystometry.

STZ-induced diabetic rats (DM) presented detrusor underactivity with significantly longer micturition interval, larger residual urine and bladder capacity, and decreased micturition pressure on awake cystometry than sham. The injection of MSCs reduced apoptosis (TUNEL) and restored muscle layer on H&E and Masson-Trichrome staining. GFP-tagged stem cells were co-stained in smooth muscle (α-SMA) and vascular pericytes (CD31). Desmin and NG2 stain (muscle specific markers) showed that transplanted MSCs were dominantly identified at myocytes. Particularly, apoptotic damage in the IC bladder was paralleled with up-regulation of Casp7, Tnf, and Sod2. In comparison with UC-MSCs, our MSC transplanted group presented superior therapeutic effect with less non-voiding contraction (stable intravesical pressure) and shortened micturition interval. However, therapeutic effects of stem cells became insignificant on long-term (both 2 and 4 weeks) follow-up. 
Of note,  injection of MSCs significantly not only improved the bladder voiding parameters but also reversed the histological and gene expression alternations characteristic for diabetic detrusor underactivity bladder.

The functional parameters of MSCs treated rats showed nearly normalized level of control rats in terms of micturition interval, bladder capacity, micturition pressure and number of non-voiding contractions. Furthermore inflammation, apoptosis and fibrosis of the bladder improved in the MSCs treated rats.
Through integrative data analysis, we identified MSCs is a novel finding that may have new treatment in diabetic detrusor underactivity rat model.

We established diabetic DUA model with STZ injection in rats. Transplantation of human ESCs derived M-MSC ishowed the possibility of therapeutic effect on established models. It is estimated that M-MSCs differentiate into myocyte and perivascular structures. Further study to identify differentiation and reveal the exact mechanism of M-MSCs is needed.