Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium.
Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium.
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DOI：
10.1016/j.ijcard.2015.05.020
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发表时间：
2015-08-01
影响因子：
3.5
通讯作者：
Tang Y
中科院分区：
文献类型：
--
作者：
Wang Y;Zhang L;Li Y;Chen L;Wang X;Guo W;Zhang X;Qin G;He SH;Zimmerman A;Liu Y;Kim IM;Weintraub NL;Tang Y
诱导多能干细胞（iPS）在缺血组织中表现出增强的存活和增殖。然而，iPS细胞的治疗应用受到其致瘤潜力的限制。我们假设iPS细胞可以通过外泌体/微泡将细胞保护信号传递给心肌细胞。从条件培养基中纯化从小鼠心脏成纤维细胞（CF）衍生的iPS细胞（iPS-exo）分泌的外泌体/微囊泡，并通过电子显微照片、颗粒跟踪分析仪的尺寸分布和ζ电位以及外泌体标记物CD 63和Tsg 101的蛋白质表达来确认。我们观察到外泌体处于低zeta电位，并且容易聚集。温度影响zeta电位（23°C时为−14~− 15 mV，37°C时为− 24 mV）。iPS-exo的摄取通过抑制caspase 3/7的活化来保护H9 C2细胞免受H2 O2诱导的氧化应激（P<0.05，n=6）。重要的是，iPS-exo治疗可以通过在再灌注前心肌内注射到小鼠缺血心肌中来保护免受心肌缺血/再灌注（MIR）损伤。此外，iPS-exo在体外向H9 C2心肌细胞递送心脏保护性miRNAs，包括nanog调节的miR-21和HIF-1α调节的miR-210。由iPS细胞分泌的外泌体/微泡在MIR的情况下非常有效地将细胞保护信号传递给心肌细胞。iPS-exo因此代表了新的生物纳米颗粒，其提供iPS细胞治疗的益处而没有致瘤性的风险，并且可以潜在地用作“现成”疗法以在诸如MIR的条件下拯救缺血性心肌细胞。
Induced pluripotent stem cells (iPS) exhibit enhanced survival and proliferation in ischemic tissues. However, the therapeutic application of iPS cells is limited by their tumorigenic potential. We hypothesized that iPS cells can transmit cytoprotective signals to cardiomyocytes via exosomes/microvesicles. Exosomes/microvesicles secreted from mouse cardiac fibroblast (CF)-derived iPS cells (iPS-exo) were purified from conditioned medium and confirmed by electron micrograph, size distribution and zeta potential by particle tracking analyzer and protein expression of the exosome markers CD63 and Tsg101. We observed that exosomes are at low zeta potential, and easily aggregate. Temperature affects zeta potential (−14~−15mV at 23°C vs −24mV at 37°C). The uptake of iPS-exo protects H9C2 cells against H2O2-induced oxidative stress by inhibiting caspase 3/7 activation (P<0.05, n=6). Importantly, iPS-exo treatment can protect against myocardial ischemia/reperfusion (MIR) injury via intramyocardially injection into mouse ischemic myocardium before reperfusion. Furthermore, iPS-exo deliver cardioprotective miRNAs, including nanog-regulated miR-21 and HIF-1α-regulated miR-210, to H9C2 cardiomyocytes in vitro. exosomes/microvesicles secreted by iPS cells are very effective at transmitting cytoprotective signals to cardiomyocytes in the setting of MIR. iPS-exo thus represent novel biological nanoparticles that offer the benefits of iPS cell therapy without the risk of tumorigenicity and can potentially serve as an “ off-the-shelf” therapy to rescue ischemic cardiomyocytes in conditions such as MIR.