Human Induced Pluripotent Stem Cell-Derived Microvesicles Transmit RNAs and Proteins to Recipient Mature Heart Cells Modulating Cell Fate and Behavior
Human Induced Pluripotent Stem Cell-Derived Microvesicles Transmit RNAs and Proteins to Recipient Mature Heart Cells Modulating Cell Fate and Behavior
复制标题
DOI：
10.1002/stem.2078
复制
发表时间：
2015-09-01
期刊：
影响因子：
5.2
通讯作者：
Zuba-Surma, Ewa K.
中科院分区：
文献类型：
--
作者：
Bobis-Wozowicz, Sylwia;Kmiotek, Katarzyna;Zuba-Surma, Ewa K.
微泡是由正常细胞和活化细胞释放的细胞质片段，是细胞间通讯的重要介质。尽管人类诱导多能干细胞（hiPSC）参与组织修复的能力正日益被认可，但hiPSC衍生的MV（hiPSC-MV）在这方面的用途仍然未知。因此，我们研究了hiPSC-MV将包括mRNA、微小RNA（miRNA）和蛋白质的生物活性分子转移到成熟靶细胞如心脏间充质基质细胞（cMSC）的能力，并且我们接下来分析了hiPSC-MV对此类靶细胞的命运和行为的影响。结果显示，在无血清和无饲养层条件下培养的无整合hiPSC衍生的hiPSC-MV富含源自亲本细胞的mRNA、miRNA和蛋白质;然而，表达水平在供体细胞和MV之间变化。重要的是，我们发现通过hiPSC-MV转移hiPSC组分影响靶细胞的转录组和蛋白质组谱，并对cMSC产生增殖和保护作用，并增强其心脏和内皮分化潜力。hiPSC-MV还从遗传修饰的hiPSC转移外源转录物，这为未来增强MV含量的策略开辟了新的前景。我们的结论是，hiPSC-MV是将iPSC属性转移到成年体细胞的有效载体，并且hiPSC-MV介导的RNA和蛋白质水平转移到受损组织可用于治疗性组织修复。在这项研究中，我们首次提出了一个新的概念，即使用hiPSCs作为组织再生的安全脱细胞生物活性衍生物的来源。
Microvesicles (MVs) are membrane-enclosed cytoplasmic fragments released by normal and activated cells that have been described as important mediators of cell-to-cell communication. Although the ability of human induced pluripotent stem cells (hiPSCs) to participate in tissue repair is being increasingly recognized, the use of hiPSC-derived MVs (hiPSC-MVs) in this regard remains unknown. Accordingly, we investigated the ability of hiPSC-MVs to transfer bioactive molecules including mRNA, microRNA (miRNA), and proteins to mature target cells such as cardiac mesenchymal stromal cells (cMSCs), and we next analyzed effects of hiPSC-MVs on fate and behavior of such target cells. The results show that hiPSC-MVs derived from integration-free hiPSCs cultured under serum-free and feeder-free conditions are rich in mRNA, miRNA, and proteins originated from parent cells; however, the levels of expression vary between donor cells and MVs. Importantly, we found that transfer of hiPSC components by hiPSC-MVs impacted on transcriptome and proteomic profiles of target cells as well as exerted proliferative and protective effects on cMSCs, and enhanced their cardiac and endothelial differentiation potential. hiPSC-MVs also transferred exogenous transcripts from genetically modified hiPSCs that opens new perspectives for future strategies to enhance MV content. We conclude that hiPSC-MVs are effective vehicles for transferring iPSC attributes to adult somatic cells, and hiPSC-MV-mediated horizontal transfer of RNAs and proteins to injured tissues may be used for therapeutic tissue repair. In this study, for the first time, we propose a new concept of use of hiPSCs as a source of safe acellular bioactive derivatives for tissue regeneration.