Abstract
BackgroundDiabetic cystopathy (DCP) is a chronic complication of diabetes mainly within the submucosal and muscular layers of the bladder due to the hyperglycemia-induced ischemia. As no effective therapies are currently available, the administration of optimized mesenchymal stem cells (MSCs) provides a potential treatment of DCP. Thus far, new strategy, such as genetic modification of MSCs, has been developed and has shown promising outcomes of various disorders.MethodsThis study was conducted using integrin-linked kinase (ILK) gene-modified bone marrow-derived stem cells (BMSCs) for streptozotocin (STZ)-induced diabetic cystopathy in a rat model. In total, 68 male Sprague-Dawley rats were randomized into five groups: sham control (control group, n = 10); DCP model alone (DM group, n = 10); DCP rats intravenously treated with BMSCs (BMSC group, n = 16); DCP rats accepted adenoviral vector-infected BMSCs (Ad-null-BMSC group, n = 16) and DCP rats accepted ILK adenoviral vector-infected BMSCs (Ad-ILK-BMSC group, n = 16). Diabetic rats accepted cell transplantation in the experimental group (2 rats per group) were sacrificed for the bladder tissue on the third day, 7th day, and 14th day of treatment respectively ahead of schedule. At 4 weeks after treatment, all rats in five groups accepted urodynamic studies to evaluate bladder function and were sacrificed for bladder tissue.ResultsOur data showed that the underactive bladder function was significantly improved in DCP rats intravenously treated with ILK gene-modified BMSCs compared to those in the DM, BMSCs, and Ad-null-BMSC group. Meanwhile, we found that gene-modified BMSC treatment significantly promoted the activation of the AKT/GSK-3β pathway by increasing phosphorylation and led to the enhancement of survival. In addition, the expression levels of angiogenesis-related protein vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and stromal cell-derived factor-1 (SDF-1) were significantly higher in the Ad-ILK-BMSC group than that in the DM, BMSCs, and Ad-null-BMSC group as assessed by enzyme-linked immunosorbent assay and western blot. As two indicators of vascular endothelial cell markers, the expression of von Willebrand factor (vWF) and CD31 by western blot and immunofluorescent staining revealed that the percentage of the vascular area of the bladder tissue significantly increased in Ad-ILK-BMSC group compared with the BMSCs and Ad-null-BMSC group on the 14th day of treatment. Histological and immunohistochemical staining (hematoxylin and eosin (HE), vWF, Ki67, and TUNNEL) on the bladder tissue revealed statistically different results between groups.ConclusionILK gene-modified BMSCs restored the bladder function and histological construction via promoting the process of angiogenesis and protecting cells from high glucose-associated apoptosis in STZ-induced DCP rat model, which provides a potential for the treatment of patients with DCP.
Highlights
Diabetic cystopathy (DCP) is a chronic complication of diabetes mainly within the submucosal and muscular layers of the bladder due to the hyperglycemia-induced ischemia
Huang et al Stem Cell Research & Therapy (2020) 11:278 (Continued from previous page) western blot and immunofluorescent staining revealed that the percentage of the vascular area of the bladder tissue significantly increased in adenovirus vector (Ad)-integrin-linked kinase (ILK)-bone marrow-derived stem cells (BMSCs) group compared with the BMSCs and Ad-null-BMSC group on the 14th day of treatment
After transfection with adenovirus for 72 h, the results of quantitative real-time polymerase chain reaction (qRT-PCR) and western blot showed that the mRNA and protein expression levels of ILK in the Ad-ILK-BMSC group were significantly higher than that in the control group (BMSCs) and Adnull-BMSC group (Fig. 2a, c, and d). These results demonstrated that ILK was successfully overexpressed in BMSCs
Summary
Diabetic cystopathy (DCP) is a chronic complication of diabetes mainly within the submucosal and muscular layers of the bladder due to the hyperglycemia-induced ischemia. As no effective therapies are currently available, the administration of optimized mesenchymal stem cells (MSCs) provides a potential treatment of DCP. Diabetic cystopathy (DCP) is likely the most common complication affecting well over 50% of diabetic individuals and a main cause of urinary tract infection in the world. DCP treatment has mostly focused on reducing infection and hydronephrosis from uroschesis in the chronic phase. Medicine and surgical therapies have provided promising results in clinical practice, long-term follow-up results have shown that these treatment options are unreliable with obvious adverse effects and create a higher long-term socioeconomic burden [3]. Around the world, there has been considerable interest in improving underactive bladder associated with DCP via bladder blood flow [8]
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