Kim Yeong Hwan, Jung Euiyoung, Im Gwang-Bum, Kim Yu-Jin, Kim Sung-Won, Jeong Gun-Jae, Jang Young Charles, Park Kyung Min, Kim Dong-Ik, Yu Taekyung, Bhang Suk Ho
School of Chemical Engineering, Sungkyunkwan University, Suwon, 440-746, Republic of Korea.
Department of Chemical Engineering, College of Engineering, Kyung Hee University, Yongin, 17104, Republic of Korea.
Nano Converg. 2020 Oct 16;7(1):34. doi: 10.1186/s40580-020-00244-5.
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.
基于人脂肪来源干细胞（hADSCs）的细胞疗法是一种已知的诱导缺血性疾病血管生成的潜在治疗方法。然而，直接注射hADSCs的治疗效果受到给药后细胞活力低和细胞植入不良的限制。为了改善这种方法的效果，已使用各种类型的纳米颗粒来提高hADSC移植的治疗效果。尽管纳米颗粒具有优势，但其副作用，如基于纳米颗粒不可降解特性的遗传损伤和潜在的肿瘤发生，限制了纳米颗粒在临床应用中的应用。在此，我们设计了一种能够进行pH选择性降解的过渡金属基无机纳米团簇（ps-TNC），旨在增强基于hADSC的小鼠后肢缺血治疗。我们设计的ps-TNC在低pH条件下会发生降解，从而仅在被内吞进入内体后才释放金属离子。为了消除传统hADSC注射和纳米颗粒不可降解特性的局限性，我们收集了经ps-TNC处理的hADSCs的条件培养基（CM）并将其施用于缺血性损伤部位。我们发现过渡金属离子在细胞内的增加会上调缺氧诱导因子1α，其可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。基于该分子机制，经ps-TNC处理的hADSCs分泌的VEGF和bFGF与未处理细胞相比有显著改善。将从经ps-TNC处理的hADSCs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hADSCs收集的CM的组（CM组）相比，损伤部位的血管生成显著改善，肢体挽救情况改善，肌肉退化减少。这项研究提出了一种新策略，将已知的血管生成分子机制与传统干细胞治疗的改进以及现代基于纳米颗粒方法中仍然存在的一些局限性的规避相结合。
