Therapeutic Efficacy of Cryopreserved, Allogeneic Extracellular Vesicles for Treatment of Acute Myocardial Infarction.
Therapeutic Efficacy of Cryopreserved, Allogeneic Extracellular Vesicles for Treatment of Acute Myocardial Infarction.
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DOI：
10.1536/ihj.20-224
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发表时间：
2021-03-30
影响因子：
1.5
通讯作者：
Atluri P
中科院分区：
文献类型：
--
作者：
Chung JJ;Kim ST;Zaman S;Helmers MR;Arisi MF;Li EC;Tran Z;Chen CW;Altshuler P;Chen M;Burdick JA;Atluri P
来源于内皮祖细胞（EPC）的细胞外囊泡（EV）已被确定为急性心肌梗死的一种新疗法，有望立即“现货”交付。早期经验表明，从同种异体来源输送电动汽车是安全的。然而，这种疗法的临床转化需要保证冷冻保存后的EV稳定性和对来自异体供体的EV没有不良免疫反应。因此，有必要对同种异体ev冷库后的生物活性进行更多的研究，以建立其广泛临床应用的质量标准。因此，在这项研究中，我们的目的是证明在异基因受体中递送冷冻保存的ev作为治疗急性心肌梗死的安全性和有效性。在本研究中，我们分析了同种异体内皮细胞衍生的ev在- 80°C下储存2个月后的心脏保护作用，使用剪切稀释凝胶（STG）作为体内递送载体。通过纳米颗粒跟踪分析、质谱分析和纳米滴分析，观察到EV大小、蛋白质组和核酸货物分别保持稳定。在心肌梗死（MI）大鼠模型中，在心肌梗死（MI）后4周，与磷酸盐缓冲盐水（PBS）和STG对照组相比，新鲜和先前冷冻的STG EVs在心肌收缩力、血管生成和疤痕厚度方面均有改善。病理分析和流式细胞术显示，当组织暴露于由异体供体细胞汇集的ev时，炎症和免疫的上调很小。同种异体epc - ev在心肌梗死后模型中至少冷冻保存2个月后，可引起最小的免疫活性并保持治疗效果。
Extracellular vesicles (EV) that are derived from endothelial progenitor cells (EPC) have been determined to be a novel therapy for acute myocardial infarction, with a promise for immediate “off-the-shelf” delivery. Early experience suggests delivery of EVs from allogeneic sources is safe. Yet, clinical translation of this therapy requires assurances of both EV stability following cryopreservation and absence of an adverse immunologic response to EVs from allogeneic donors. Thus, more bioactivity studies on allogeneic EVs after cold storage are necessary to establish quality standards for its widespread clinical use. Thus, in this study, we aimed to demonstrate the safety and efficacy in delivering cryopreserved EVs in allogeneic recipients as a therapy for acute myocardial infarction. In this present study, we have analyzed the cardioprotective effects of allogeneic EPC-derived EVs after storage at −80°C for 2 months, using a shear-thinning gel (STG) as an in vivo delivery vehicle. EV size, proteome, and nucleic acid cargo were observed to remain steady through extended cryopreservation via nanoparticle tracking analysis, mass spectrometry, and nanodrop analysis, respectively. Fresh and previously frozen EVs in STG were delivered intramyocardially in a rat model of myocardial infarction (MI), with both showing improvements in contractility, angiogenesis, and scar thickness in comparison to phosphate-buffered saline (PBS) and STG controls at 4 weeks post-MI. Pathologic analyses and flow cytometry revealed minimal inflammatory and immune upregulation upon exposure of tissue to EVs pooled from allogeneic donor cells. Allogeneic EPC-EVs have been known to elicit minimal immune activity and retain therapeutic efficacy after at least 2 months of cryopreservation in a post-MI model.