Abstract 10791: Regeneration-Associated Cells Derived Exosomes Beneficial Than Mesenchymal Stromal Cells Derived Exosome in the Context of Myocardial Ischemia-Injury
Abstract 10791: Regeneration-Associated Cells Derived Exosomes Beneficial Than Mesenchymal Stromal Cells Derived Exosome in the Context of Myocardial Ischemia-Injury
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摘要 10791：在心肌缺血损伤的情况下，再生相关细胞衍生的外泌体比间充质基质细胞衍生的外泌体有益
DOI：
10.1161/circ.144.suppl_1.10791
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发表时间：
2021
期刊：
影响因子：
37.8
通讯作者：
Asahara Takayuki
中科院分区：
文献类型：
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作者：
Salybekov Amankeldi A;Salybekova Ainur;Sheng Yin;Kobayashi Shuzo;Asahara Takayuki
前言：促炎症细胞如巨噬细胞1、T细胞和原始内皮祖细胞的血管生成调节将其表型转变为促再生细胞，如血管生成内皮祖细胞、M2巨噬细胞和REG T细胞，也称为再生相关细胞(RAC)。在此，我们比较了RAC来源的细胞外小泡(RACev)和MSC来源的EV(MSCev)对心肌缺血再灌注损伤(IRI)的治疗效果。通过纳米跟踪分析和CD9、CD63、Alix的表达来表征EVS的数量和质量。对EVS miR进行测序，并使用TargetScan和miRBase验证再生负责的miR。检测RACev和MSCev的同种异体免疫应答。通过体外HUVECs增殖/细胞周期分析评价RACev和MSCev的功能，并在心肌缺血再灌注模型中重复(IRI后30min、d1和d3)系统注射RACev和MSCev。结果：纳米追踪分析显示RACev和MSCev在数量上存在显著差异(P=0.03)。系统注射RAC(5x105)衍生EVS可改善心功能，如射血分数(P=0.005)。组织学上，RACev移植组较MSCev移植组间质纤维化程度减轻，毛细血管密度增加(P=0.05)。这些有益的作用与血管生成、抗炎、心肌生成和抗纤维化相关的miRs在RACev中的显著表达相结合，而在MSCev中则不表达。在活体发光和标记的EVS组织学跟踪分析中，RACev比MSCev更优先地在IRI心肌中积聚(P=0.01)。免疫表型分析证实了MSCev和RACevv相似的免疫调节作用。结论：重复系统移植RACev通过向缺血组织传递关键的血管生成、抗纤维化、抗炎、心肌生成和抗凋亡相关miRs而增强心功能。
Introduction:Vasculogenic conditioning of pro-inflammatory cells such as macrophages type 1, T cells, and primitive EPCs shifted their phenotype to pro-regenerative cells such as vasculogenic EPCs, M2 macrophages, and reg T cells, also known as regeneration-associated cells (RACs). Here, we investigated therapeutic efficacy of RAC-derived extracellular vesicles (RACev) in comparison with MSC-derived EVs (MSCev) in the context of myocardial ischemia-reperfusion injury (IRI).Methods:RACev and MSCev were isolated via ultracentrifugation. EVs quantity and quality were characterized by nanotracking analysis and CD9, CD63, Alix expression. EVs miR was sequenced and regenerative responsible miRs were validated using TargetScan and miRBase. Allogeneic immune response to the RACev and MSCev were evaluated. The function of RACev and MSCev were evaluated using HUVECs proliferation/cell-cycle assaysin vitro,and repetitive (30min, d1, and d3 after IRI) systemic infusion with either RACev or MSCev in a myocardial IRI model.Results:Nanotracking analysis showed significant differences in quantity RACev vs. MSC (P= 0.03).In vitro, RACev markedly enhanced cell viability, proliferation, and migration of HUVECs in a dose-dependent manner compared to MSCev. Systemic injection of RACs (5x105) derived EVs improved cardiac functions such as ejection fraction (P= 0.005) than MSCev treated group. In histology, RACev transplanted group showed less interstitial fibrosis and enhanced capillary densities (P =0.05) compared to MSCev. These beneficial effects are coupled with significant expression of angiogenesis, anti-inflammation, cardiomyogenesis, and anti-fibrosis-related miRs in RACev but not in MSCev.In vivobioluminescence and labeled EVs histology tracking analyses depicted preferential accumulation of RACev into the IRI myocardium (P=0.01) than MSCev. Immune phenotyping analysis confirmed similar immunomodulatory effects of MSCev and RACev.Conclusion:Repetitive systemic transplantation of RACev is superior to MSCev in terms of cardiac function enhancements via crucial angiogenesis, anti-fibrosis, anti-inflammation, cardiomyogenesis, and anti-apoptosis-related miRs delivery to the ischemic tissue.