Wang Gong, Zhuo Zhongxiong, Yang Bin, Wu Shengzheng, Xu Yali, Liu Zheng, Tan Kaibin, Xia Hongmei, Wang Xiaoyan, Zou Linru, Gan Ling, Gao Yunhua
Department of Ultrasound, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
Department of Ultrasound Diagnostics, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, China.
Ultrasound Med Biol. 2015 Nov;41(11):2977-89. doi: 10.1016/j.ultrasmedbio.2015.07.002. Epub 2015 Aug 28.
Bone marrow stromal cell (BMSC) transplantation can successfully treat diabetic nephropathy (DN), but the lack of a specific homing place for intravenously injected cells limits the effective implementation of stem cell therapies. The migration and survival of transplanted BMSCs are determined by inflammatory reactions in the local kidney micro-environment. We tested the hypothesis that microbubble-mediated diagnostic ultrasound irradiation could provide a suitable micro-environment for BMSC delivery and retention in DN therapy. In this study, red fluorescent protein-labeled BMSCs were administered combined with microbubbles to streptozotocin-induced DN rats 4 wk after diabetes onset. We observed enhanced BMSC homing and retention in microbubble-mediated diagnostic ultrasound-irradiated kidneys compared with the contralateral kidneys on days 1 and 3 post-treatment. The results from immunohistochemical analysis, Western blot and enzyme-linked immunosorbent assay indicated that the local and transient expression of various chemo-attractants (i.e., cytokines, integrins and trophic factors) found to promote BMSC homing was much higher than observed in non-treated kidneys. The local capillary endothelium rupture observed by transmission electron microscopy may account for local micro-environment changes. Histopathologic analysis revealed no signs of kidney damage. These results confirmed that renal micro-environment changes caused by appropriate microbubble-mediated diagnostic ultrasound irradiation may promote BMSC homing ability to the diabetic kidney without renal toxicity and cell damage. This non-invasive and effective technique may be a promising method for BMSC transplantation therapy.
骨髓基质细胞（BMSC）移植能够成功治疗糖尿病肾病（DN），但静脉注射细胞缺乏特定的归巢位点限制了干细胞疗法的有效实施。移植的BMSC的迁移和存活取决于局部肾脏微环境中的炎症反应。我们验证了这样一个假设，即微泡介导的诊断性超声照射可为DN治疗中BMSC的递送和留存提供适宜的微环境。在本研究中，在糖尿病发病4周后，将红色荧光蛋白标记的BMSC与微泡联合给予链脲佐菌素诱导的DN大鼠。我们观察到，与对侧肾脏相比，在治疗后第1天和第3天，微泡介导的诊断性超声照射的肾脏中BMSC的归巢和留存增强。免疫组织化学分析、蛋白质印迹法和酶联免疫吸附测定的结果表明，发现可促进BMSC归巢的各种趋化因子（即细胞因子、整合素和营养因子）的局部和短暂表达远高于未治疗的肾脏。透射电子显微镜观察到的局部毛细血管内皮破裂可能是局部微环境变化的原因。组织病理学分析未发现肾脏损伤迹象。这些结果证实，适当的微泡介导的诊断性超声照射引起的肾脏微环境变化可能促进BMSC向糖尿病肾脏的归巢能力，而无肾脏毒性和细胞损伤。这种非侵入性且有效的技术可能是BMSC移植治疗的一种有前景的方法。
