PMID- 32650831 OWN - NLM STAT- MEDLINE DCOM- 20210618 LR - 20211204 IS - 1757-6512 (Electronic) IS - 1757-6512 (Linking) VI - 11 IP - 1 DP - 2020 Jul 10 TI - Therapeutic effect of integrin-linked kinase gene-modified bone marrow-derived mesenchymal stem cells for streptozotocin-induced diabetic cystopathy in a rat model. PG - 278 LID - 10.1186/s13287-020-01795-4 [doi] LID - 278 AB - BACKGROUND: 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. Thus far, new strategy, such as genetic modification of MSCs, has been developed and has shown promising outcomes of various disorders. METHODS: This 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. RESULTS: Our 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-3beta 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. CONCLUSION: ILK 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. FAU - Huang, Yi AU - Huang Y AD - Department of Urology, Nanjing Medical University Second Affiliated Hospital, No.121 Jiangjiayuan Road, Gulou District, Nanjing, 21000, China. AD - Department of Urology, Affiliated Hospital, Jiangnan University, Wuxi, China. FAU - Gao, Jie AU - Gao J AD - Department of Urology, Nanjing Medical University Second Affiliated Hospital, No.121 Jiangjiayuan Road, Gulou District, Nanjing, 21000, China. FAU - Zhou, Yiduo AU - Zhou Y AD - Department of Urology, Nanjing Medical University Second Affiliated Hospital, No.121 Jiangjiayuan Road, Gulou District, Nanjing, 21000, China. FAU - Wu, Shuo AU - Wu S AD - Department of Urology, Nanjing Medical University Second Affiliated Hospital, No.121 Jiangjiayuan Road, Gulou District, Nanjing, 21000, China. FAU - Shao, Yunpeng AU - Shao Y AD - Department of Urology, Nanjing Medical University Second Affiliated Hospital, No.121 Jiangjiayuan Road, Gulou District, Nanjing, 21000, China. FAU - Xue, Haoliang AU - Xue H AD - Department of Urology, Nanjing Medical University Second Affiliated Hospital, No.121 Jiangjiayuan Road, Gulou District, Nanjing, 21000, China. AD - Department of Urology, Jiangdu People's Hospital of Yangzhou, Yangzhou, China. FAU - Shen, Baixin AU - Shen B AD - Department of Urology, Nanjing Medical University Second Affiliated Hospital, No.121 Jiangjiayuan Road, Gulou District, Nanjing, 21000, China. FAU - Ding, Liucheng AU - Ding L AUID- ORCID: 0000-0002-0610-2898 AD - Department of Urology, Nanjing Medical University Second Affiliated Hospital, No.121 Jiangjiayuan Road, Gulou District, Nanjing, 21000, China. Lancet110@126.com. FAU - Wei, Zhongqing AU - Wei Z AD - Department of Urology, Nanjing Medical University Second Affiliated Hospital, No.121 Jiangjiayuan Road, Gulou District, Nanjing, 21000, China. weizq1@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200710 PL - England TA - Stem Cell Res Ther JT - Stem cell research & therapy JID - 101527581 RN - 0 (Vascular Endothelial Growth Factor A) RN - 5W494URQ81 (Streptozocin) RN - EC 2.7.1.- (integrin-linked kinase) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) SB - IM MH - Animals MH - Bone Marrow MH - Bone Marrow Cells MH - *Diabetes Mellitus, Experimental/therapy MH - Glycogen Synthase Kinase 3 beta MH - Humans MH - Male MH - *Mesenchymal Stem Cell Transplantation MH - *Mesenchymal Stem Cells MH - Protein Serine-Threonine Kinases MH - Rats MH - Rats, Sprague-Dawley MH - Streptozocin MH - Vascular Endothelial Growth Factor A PMC - PMC7350700 OTO - NOTNLM OT - Angiogenesis OT - Antiapoptosis OT - Bone marrow-derived mesenchymal stem cells OT - Diabetic cystopathy OT - Integrin-linked kinase OT - Proliferation COIS- The authors declare that they have no competing interests. EDAT- 2020/07/12 06:00 MHDA- 2021/06/22 06:00 PMCR- 2020/07/10 CRDT- 2020/07/12 06:00 PHST- 2020/05/09 00:00 [received] PHST- 2020/06/29 00:00 [accepted] PHST- 2020/06/16 00:00 [revised] PHST- 2020/07/12 06:00 [entrez] PHST- 2020/07/12 06:00 [pubmed] PHST- 2021/06/22 06:00 [medline] PHST- 2020/07/10 00:00 [pmc-release] AID - 10.1186/s13287-020-01795-4 [pii] AID - 1795 [pii] AID - 10.1186/s13287-020-01795-4 [doi] PST - epublish SO - Stem Cell Res Ther. 2020 Jul 10;11(1):278. doi: 10.1186/s13287-020-01795-4.