Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
Joint Unit for cardiovascular Repair Instituto de Investigación Sanitaria La Fe-Centro de Investigación Príncipe Felipe, Valencia, Spain.
Stem Cells. 2017 Jul;35(7):1747-1759. doi: 10.1002/stem.2618. Epub 2017 Apr 24.
Insufficient vessel growth associated with ischemia remains an unresolved issue in vascular medicine. Mesenchymal stem cells (MSCs) have been shown to promote angiogenesis via a mechanism that is potentiated by hypoxia. Overexpression of hypoxia inducible factor (HIF)-1α in MSCs improves their therapeutic potential by inducing angiogenesis in transplanted tissues. Here, we studied the contribution of exosomes released by HIF-1α-overexpressing donor MSCs (HIF-MSC) to angiogenesis by endothelial cells. Exosome secretion was enhanced in HIF-MSC. Omics analysis of miRNAs and proteins incorporated into exosomes pointed to the Notch pathway as a candidate mediator of exosome communication. Interestingly, we found that Jagged1 was the sole Notch ligand packaged into MSC exosomes and was more abundant in HIF-MSC than in MSC controls. The addition of Jagged1-containing exosomes from MSC and HIF-MSC cultures to endothelial cells triggered transcriptional changes in Notch target genes and induced angiogenesis in an in vitro model of capillary-like tube formation, and both processes were stimulated by HIF-1α. Finally, subcutaneous injection of Jagged 1-containing exosomes from MSC and HIF-MSC cultures in the Matrigel plug assay induced angiogenesis in vivo, which was more robust when they were derived from HIF-MSC cultures. All Jagged1-mediated effects could be blocked by prior incubation of exosomes with an anti-Jagged 1 antibody. All together, the results indicate that exosomes derived from MSCs stably overexpressing HIF-1α have an increased angiogenic capacity in part via an increase in the packaging of Jagged1, which could have potential applications for the treatment of ischemia-related disease. Stem Cells 2017;35:1747-1759.
与缺血相关的血管生成不足仍然是血管医学中的一个未解决的问题。间充质干细胞 (MSCs) 已被证明通过一种被低氧增强的机制促进血管生成。在 MSCs 中过表达缺氧诱导因子 (HIF)-1α 通过诱导移植组织中的血管生成来提高其治疗潜力。在这里，我们研究了由过表达 HIF-1α 的供体 MSC（HIF-MSC）释放的外泌体对内皮细胞血管生成的贡献。HIF-MSC 中外泌体的分泌得到增强。外泌体中整合的 miRNA 和蛋白质的组学分析表明 Notch 途径是外泌体通讯的候选介质。有趣的是，我们发现 Jagged1 是唯一包装到 MSC 外泌体中的 Notch 配体，并且在 HIF-MSC 中比在 MSC 对照中更丰富。从 MSC 和 HIF-MSC 培养物中添加含有 Jagged1 的外泌体到内皮细胞中，触发了 Notch 靶基因的转录变化，并在体外毛细血管样管形成模型中诱导血管生成，这两个过程都受到 HIF-1α 的刺激。最后，在 Matrigel plugs 实验中，MSC 和 HIF-MSC 培养物中含有 Jagged1 的外泌体的皮下注射在体内诱导血管生成，当它们来自 HIF-MSC 培养物时更为明显。所有 Jagged1 介导的作用都可以通过用抗 Jagged1 抗体预先孵育外泌体来阻断。总而言之，这些结果表明，稳定过表达 HIF-1α 的 MSC 衍生的外泌体具有增强的血管生成能力，部分原因是 Jagged1 的包装增加，这可能对缺血相关疾病的治疗具有潜在的应用价值。Stem Cells 2017;35:1747-1759.
