Exosomes Derived from Human Induced Pluripotent Stem Cells-Endothelia Cells Promotes Postnatal Angiogenesis in Mice Bearing Ischemic Limbs
Exosomes Derived from Human Induced Pluripotent Stem Cells-Endothelia Cells Promotes Postnatal Angiogenesis in Mice Bearing Ischemic Limbs
复制标题
源自人类诱导多能干细胞-内皮细胞的外泌体促进四肢缺血小鼠的产后血管生成
DOI：
10.7150/ijbs.28392
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发表时间：
2019
影响因子：
9.2
通讯作者：
Lan Zhang
中科院分区：
文献类型：
--
作者：
Meng Ye;Qihong Ni;Haozhe Qi;Xin Qian;Jiaquan Chen;Xiangjiang Guo;Maoran Li;Yiping Zhao;Guanhua Xue;Haoyu Deng;Lan Zhang
诱导多能干细胞（iPSC）衍生的内皮细胞（EC）是缺血性疾病的一种新的治疗选择。虽然这种新疗法的详细机制仍然未知，但新出现的证据表明，来源于hiPSC-EC的外泌体在这种方法中起着关键作用。在这项研究中，我们首先从iPSCs-EC中分离和表征了外泌体（hiPSC-EC-Exo），并确定了hiPSC-EC-Exo在新生血管形成中的功能作用及其潜在机制。此外，我们评估了来源于hiPS-EC的外泌体在具有缺血肢体的小鼠模型中促进血管生成的作用。我们的研究结果表明，miR-199 b-5 p，一种与血管生成高度相关的miRNA，在hiPSC-EC分化过程中显著上调。在机制上，我们的研究发现，表达miR-199 b-5 p的hiPSC-EC通过Jagged-1依赖性上调HUVEC中的VEGFR 2显著促进细胞迁移、增殖和管形成。类似地，hiPSC-EC-Exo与HUVEC的共培养也导致HUVEC迁移、增殖和管形成的显著改善，表明外泌体介导的细胞间通讯以旁分泌方式可作为基于iPSC-EC的治疗的基本机制。因此，我们发现富含miR-199 b-5 p的hiPSC-EC的转移显著增强了体内缺血肢体中的微血管密度和血液灌注。总之，我们的研究首次证明了hiPSC-ECs-Exo的转移是通过促进新血管形成的机制治疗缺血性损伤的有前景的方法。
Induced pluripotent stem cell (iPSC) derived endothelial cells (ECs) is a novel therapeutic option for ischemic diseases. Although the detailed mechanism of this novel therapy remains unknown, emerging evidence has demonstrated that exosomes derived from hiPSC-ECs play a critical role in this approach. In this study, we first isolated and characterized the exosomes from iPSCs-ECs (hiPSC-EC-Exo) and determined the functional roles of hiPSC-EC-Exo in neovascularization and the underlying mechanism. Further, we evaluated the effect of exosomes derived from hiPS-ECs on promoting angiogenesis in a mouse model bearing ischemic limbs. Our results showed that miR-199b-5p, an miRNA highly associated with angiogenesis, is significantly upregulated during the differentiation of hiPSC-ECs. Mechanically, our studies found that hiPSC-ECs expressing miR-199b-5p significantly promote cell migration, proliferation and tube formation through Jagged-1-dependent upregulation of VEGFR2 in HUVECs. Similarly, coculture of hiPSC-ECs-Exo with HUVECs also resulted in a significant improvement in HUVEC migration, proliferation, and tube formation, suggesting that exosome-mediated cell-cell communication in a paracrine manner may serve as a fundamental mechanism for iPSC-EC-based treatment. Consequently, we found that the transfer of hiPSC-ECs enriched with miR-199b-5p significantly enhanced micro-vessel density and blood perfusion in ischemic limbs in vivo. Taken together, our studies were the first to demonstrate that transfer of hiPSC-ECs-Exo is a promising approach to treat ischemic injury via the mechanism of promoting neovascularization.