Regulation of intracellular transition metal ion level with a pH-sensitive inorganic nanocluster to improve therapeutic angiogenesis by enriching conditioned medium retrieved from human adipose derived stem cells.
Regulation of intracellular transition metal ion level with a pH-sensitive inorganic nanocluster to improve therapeutic angiogenesis by enriching conditioned medium retrieved from human adipose derived stem cells.
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DOI：
10.1186/s40580-020-00244-5
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发表时间：
2020-10-16
期刊：
影响因子：
11.7
通讯作者：
Bhang SH
中科院分区：
文献类型：
--
作者：
Kim YH;Jung E;Im GB;Kim YJ;Kim SW;Jeong GJ;Jang YC;Park KM;Kim DI;Yu T;Bhang SH
基于人脂肪源性干细胞（hADSC）的细胞疗法是已知的诱导缺血性疾病中的血管生成的潜在治疗方法。然而，直接hADSC注射的治疗功效受限于施用后的低细胞活力和差的细胞植入。为了改善这种方法的结果，已经利用各种类型的纳米颗粒来改善hADSC移植的治疗效果。尽管纳米颗粒具有许多优点，但由于其不可降解的特性，纳米颗粒的不利影响，如遗传损伤和潜在的肿瘤发生，阻碍了纳米颗粒在临床上的应用。在此，我们设计了一种基于过渡金属的无机纳米团簇能够pH选择性降解（ps-TNC），目的是增强基于hADSC的小鼠后肢缺血治疗。我们的ps-TNC被设计为在低pH条件下进行降解，从而仅在胞吞作用后在内体中释放金属离子。为了消除常规hADSC注射和纳米颗粒的不可降解性质两者的限制，我们从ps-TNC处理的hADSC收集条件培养基（CM）并将其施用到缺血性病变。我们发现，细胞内过渡金属离子的增量上调缺氧诱导因子1α，这可以诱导血管内皮生长因子（VEGF）和碱性成纤维细胞生长因子（bFGF）的表达。基于分子机制，ps-TNC处理的hADSC的VEGF和bFGF分泌与未处理的细胞相比显示出显著的改善。将从ps-TNC处理的hADSC收集的CM注射到小鼠后肢缺血模型中（ps-TNC-CM组），与注射从正常hADSC收集的CM的组（CM组）相比，显示病变中的血管生成显著改善，具有改善的肢体挽救和减少的肌肉变性。这项研究提出了一种新的策略，将已知的血管生成分子机制与传统干细胞治疗的改进和基于纳米颗粒的现代方法中仍然存在的一些局限性相结合。
Cell therapy based on human adipose derived stem cells (hADSCs) is a known potential therapeutic approach to induce angiogenesis in ischemic diseases. However, the therapeutic efficacy of direct hADSC injection is limited by a low cell viability and poor cell engraftment after administration. To improve the outcomes of this kind of approach, various types of nanoparticles have been utilized to improve the therapeutic efficacy of hADSC transplantation. Despite their advantages, the adverse effects of nanoparticles, such as genetic damage and potential oncogenesis based on non-degradable property of nanoparticles prohibit the application of nanoparticles toward the clinical applications. Herein, we designed a transition metal based inorganic nanocluster able of pH-selective degradation (ps-TNC), with the aim of enhancing an hADSC based treatment of mouse hindlimb ischemia. Our ps-TNC was designed to undergo degradation at low pH conditions, thus releasing metal ions only after endocytosis, in the endosome. To eliminate the limitations of both conventional hADSC injection and non-degradable property of nanoparticles, we have collected conditioned medium (CM) from the ps-TNC treated hADSCs and administrated it to the ischemic lesions. We found that intracellular increment of transition metal ion upregulated the hypoxia-inducible factor 1α, which can induce vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) expressions. Based on the molecular mechanism, the secretion of VEGF and bFGF by ps-TNC treated hADSCs showed a significant improvement compared to that of untreated cells. Injecting the CM collected from ps-TNC treated hADSCs into the mouse hindlimb ischemia model (ps-TNC-CM group) showed significantly improved angiogenesis in the lesions, with improved limb salvage and decreased muscle degeneration compared to the group injected with CM collected from normal hADSCs (CM group). This study suggests a novel strategy, combining a known angiogenesis molecular mechanism with both an improvement on conventional stem cell therapy and the circumvention of some limitations still present in modern approaches based on nanoparticles.