1 Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology , Seoul, Republic of Korea.
2 Department of Biomedical Engineering, Korea University of Science and Technology , Daejeon, Republic of Korea.
Tissue Eng Part A. 2018 Apr;24(7-8):616-630. doi: 10.1089/ten.TEA.2017.0260. Epub 2017 Sep 26.
Peripheral artery disease (PAD) is an ischemic disease characterized by reduced blood flow to the legs, feet, and hands. Human mesenchymal stem cells are an attractive cell source to treat PAD in regenerative medicine. However, in clinical applications, the use of adult stem cells has several limitations, such as low cell viability and low therapeutic efficiency. In this study, we described an innovative method of culturing three-dimensional stem cell clusters (Angiocluster™ [AC]), demonstrated the potential for ACs to differentiate into vascular cells, and assessed the synergistic effects of ACs and angiopoietin-1 (Ang-1) on angiogenesis in ischemic animal models. ACs were formed by culturing human adipose-derived stem cells (hASCs) on a maltose-binding protein-linked basic fibroblast growth factor-immobilized polystyrene surface. ACs released various angiogenic factors, such as vascular endothelial growth factor and interleukin-8, and could differentiate into endothelial lineage cells. However, ACs did not secrete Ang-1, which is an essential component of vascular maturation and anti-inflammation. ACs were combined with Ang-1 and were transplanted into the ischemic lesions of mice for 28 days. Most of the mice receiving the AC + Ang-1 treatment exhibited limb salvage and exhibited similar blood perfusion ratio compared to normal limb. The combination therapy of AC and Ang-1 enhanced angiogenic efficacy by increasing blood vessel regeneration and facilitating the implantation of stem cells into host vessels. Importantly, fibrotic collagen was observed in most of the groups after 28 days of treatment, except for the AC + Ang-1 group. This indicates that the combination therapy is synergistic in minimizing ischemic fibrosis and muscle degeneration. Our results demonstrate that the combination therapy significantly enhanced tissue regeneration and angiogenic efficacy of hASCs and may have wide applications in regenerative medicine.
外周动脉疾病（PAD）是一种以腿部、脚部和手部血流减少为特征的缺血性疾病。人类间充质干细胞是再生医学中治疗 PAD 的一种有吸引力的细胞来源。然而，在临床应用中，使用成人干细胞存在几个限制，例如细胞活力低和治疗效率低。在本研究中，我们描述了一种培养三维干细胞簇（AngioclusterTM [AC]）的创新方法，证明了 AC 分化为血管细胞的潜力，并评估了 AC 和血管生成素-1（Ang-1）在缺血动物模型中对血管生成的协同作用。AC 通过在麦芽糖结合蛋白连接的碱性成纤维细胞生长因子固定化聚苯乙烯表面上培养人脂肪来源干细胞（hASCs）形成。AC 释放各种血管生成因子，如血管内皮生长因子和白细胞介素-8，并可分化为内皮谱系细胞。然而，AC 不分泌 Ang-1，这是血管成熟和抗炎的重要组成部分。AC 与 Ang-1 结合并移植到小鼠的缺血病变部位 28 天。接受 AC+Ang-1 治疗的大多数小鼠都有肢体存活，与正常肢体相比，血液灌注率相似。AC 和 Ang-1 的联合治疗通过增加血管再生和促进干细胞植入宿主血管来增强血管生成效果。重要的是，除了 AC+Ang-1 组外，在治疗 28 天后，大多数组都观察到纤维性胶原。这表明联合治疗在最大限度地减少缺血性纤维化和肌肉变性方面具有协同作用。我们的结果表明，联合治疗显著增强了 hASCs 的组织再生和血管生成效果，可能在再生医学中有广泛的应用。
