A combination of ultrasound-targeted microbubble destruction with transplantation of bone marrow mesenchymal stem cells promotes recovery of acute liver injury
A combination of ultrasound-targeted microbubble destruction with transplantation of bone marrow mesenchymal stem cells promotes recovery of acute liver injury
复制标题
超声靶向微泡破坏与骨髓间充质干细胞移植相结合促进急性肝损伤的恢复
DOI：
10.1186/s13287-018-1098-4
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发表时间：
2018-12-29
影响因子：
7.5
通讯作者：
Du, Lianfang
中科院分区：
文献类型：
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作者：
Sun, Ting;Gao, Feng;Du, Lianfang
背景骨髓间充质干细胞(BMSCs)可为急性肝损伤(ALI)时肝细胞再生提供额外的治疗干细胞来源。然而，移植的BMSCs在肝脏归巢方面的不足限制了其应用。超声靶向微泡破坏(UTMD)已被报道促进移植的干细胞归巢到缺血心肌。本研究旨在探讨UTMD对ALI大鼠BMSCs肝归巢的促进作用，并评价其治疗效果。将表达增强型绿色荧光蛋白(EGFP)的慢病毒稳定地转染分离的BMSCs，移植后可在体内观察和定量。应用肿瘤坏死因子α和基质细胞衍生因子1(SDF-1)来验证合适的超声参数。将ALI大鼠分为对照组、BMSCs组、UTMD组和UTMD+BMSCs组。染毒后48 h检测肝组织中细胞间黏附分子1、血管细胞黏附分子1、肝细胞生长因子和单核细胞趋化蛋白1的表达水平。结果分离的大鼠骨髓间充质干细胞具有良好的成骨和成脂分化潜能，表达分化簇CD29和CD90，但不表达CD45和CD11b/c。经UTMD和/或UTMD处理后，UTMD+BMSCs组GFP标记的BMSCs数量显著高于BMSCs组(9.8 ± 2.3vs.5.2 ± 1.1个/高倍视野)。此外，还通过检测GFP mRNA的表达来评价骨髓间充质干细胞在损伤部位的归巢情况。UTMD+BMSCs组SDF-1、ICAM-1、VCAM-1、HGF和MCP-1的表达水平均高于对照组(p<； )。UTMD+BMSCs组血清生物标志物水平明显低于BMSCs组，肝细胞凋亡率明显低于BMSCs组(P均<0.05)。 结果显示，UTMD+BMSCs组肝细胞凋亡率明显低于BMSCs组。UTMD+BMSCs组肝脏病理明显减轻。结论UTMD治疗有效地诱导了细胞植入的良好微环境，从而改善了BMSCs的肝归巢，其机制可能是通过上调黏附分子和细胞因子的表达来实现的。UTMD治疗似乎是一种有效和非侵入性的方法，可以使基于BMSC的治疗在修复严重损伤的肝脏时获得更好的疗效。
BackgroundBone marrow mesenchymal stem cells (BMSCs) can provide an additional source of therapeutic stem cells for regeneration of liver cells during acute liver injury (ALI). However, the insufficient hepatic homing by the transplanted BMSCs limits their applications. Ultrasound-targeted microbubble destruction (UTMD) has been reported to promote the homing of transplanted stem cells into the ischemic myocardium. In this study, we investigated whether UTMD promotes the hepatic homing of BMSCs in ALI rats and evaluated the therapeutic effect.MethodsBMSCs were isolated from the femurs and tibias of Sprague-Dawley (SD) rats. The isolated BMSCs were stably transfected with a lentivirus expressing enhanced green fluorescent protein (EGFP) that can be visualized and quantified in vivo after transplantation. Both tumor necrosis factor α (TNF-α) and stromal cell-derived factor 1 (SDF-1) were used to verify the appropriate ultrasound parameters. The ALI rats were divided into four groups: control, BMSCs, UTMD, and UTMD + BMSCs. The protein and mRNA expression levels of SDF-1, intercellular cell adhesion molecule (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), hepatocyte growth factor (HGF), and monocyte chemotactic protein 1 (MCP-1) in the exposed livers were analyzed at 48 h after treatment. ALI recovery was determined by serum biochemical parameters and histology.ResultsThe isolated rat BMSCs demonstrated a good proliferation potential that was both osteogenic and adipogenic in differentiation and expressed cluster of differentiation (CD) 29 and CD90, but not CD45 or CD11b/c. After BMSC and/or UTMD treatment, the number of GFP-labeled BMSCs in the UTMD + BMSCs group was significantly higher than that of the BMSCs group (9.8 ± 2.3 vs. 5.2 ± 1.1/per high-power field). Furthermore, the expression of GFP mRNA was performed for evaluation of the homing rate of BMSCs in injury sites as well. In addition, the expression levels of SDF-1, ICAM-1, VCAM-1, HGF, and MCP-1 were higher (p< 0.01) in UTMD+BMSCs group. The serum levels of biomarkers were significantly lower in the UTMD + BMSCs group, and the apoptotic rate of hepatocytes in the UTMD + BMSCs group was markedly lower than that of the BMSCs group (allp< 0.05). The hepatic pathology was significantly alleviated in the UTMD + BMSCs group.ConclusionsUTMD treatment efficiently induced a favorable microenvironment for cell engraftment, resulting in improvement of hepatic homing of BMSCs, which was probably mediated through upregulation of the expression of adhesion molecules and cytokines. UTMD treatment appeared to be an effective and noninvasive approach to achieve better efficacy of BMSC-based therapy for repairing a severely injured liver.