CD146+ Endometrial-Derived Mesenchymal Stem/Stromal Cell Subpopulation Possesses Exosomal Secretomes with Strong Immunomodulatory miRNA Attributes.
CD146+ Endometrial-Derived Mesenchymal Stem/Stromal Cell Subpopulation Possesses Exosomal Secretomes with Strong Immunomodulatory miRNA Attributes.
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子宫内膜间充质干细胞/基质细胞（eMSC）的血管周围定位使它们能够感知局部和远处的组织损伤，促进组织修复和愈合。我们的假设是，eMSC的治疗作用主要是通过它们的外泌体分泌组（eMSC exo）通过靶向免疫系统和血管生成调节来发挥作用的。为此，研究人员比较了从Crude和CD146+ eMSC群体中分离的exo在炎症条件下的miRNA治疗特征和免疫调节功能。eMSC exo分析显示，原油mirna中有121个，CD146+ mirna中有88个，其中82个在两种人群中普遍存在。对eMSC exo中高度存在的mirna的Reactome和KEGG分析表明，它们参与免疫系统调节。从常见的mirna来看，四种mirna （hsa-miR-320e, hsa-miR-182-3p, hsa-miR-378g, hsa-let-7e-5p）在CD146+ eMSC exo中更富集。这些mirna参与巨噬细胞极化、T细胞活化和炎症细胞因子转录（即TNF-α、IL-1β和IL-6）的调节。在功能上，与单独刺激相比，暴露于eMSC exo的刺激巨噬细胞表现出向替代M2状态的转换，并且吞噬能力降低。然而，与单独刺激相比，eMSC exo并没有抑制刺激的人外周血单个核细胞的增殖，但显著减少了13种促炎分子的分泌。同时，两种抗炎蛋白IL-10和IL-13的分泌量增加，特别是在CD146+ eMSC EXO暴露时。我们的研究表明，eMSC，甚至CD146+亚群，拥有具有强免疫调节miRNA属性的外泌体分泌组。由此产生的证据可以作为基于eMSC exo的治疗方法解决组织炎症有害方面的基础。
The perivascular localization of endometrial mesenchymal stem/stromal cells (eMSC) allows them to sense local and distant tissue damage, promoting tissue repair and healing. Our hypothesis is that eMSC therapeutic effects are largely exerted via their exosomal secretome (eMSC EXOs) by targeting the immune system and angiogenic modulation. For this purpose, EXOs isolated from Crude and CD146+ eMSC populations were compared for their miRNA therapeutic signatures and immunomodulatory functionality under inflammatory conditions. eMSC EXOs profiling revealed 121 in Crude and 88 in CD146+ miRNAs, with 82 commonly present in both populations. Reactome and KEGG analysis of miRNAs highly present in eMSC EXOs indicated their involvement among others in immune system regulation. From the commonly present miRNAs, four miRNAs (hsa-miR-320e, hsa-miR-182-3p, hsa-miR-378g, hsa-let-7e-5p) were more enriched in CD146+ eMSC EXOs. These miRNAs are involved in macrophage polarization, T cell activation, and regulation of inflammatory cytokine transcription (i.e., TNF-α, IL-1β, and IL-6). Functionally, stimulated macrophages exposed to eMSC EXOs demonstrated a switch towards an alternate M2 status and reduced phagocytic capacity compared to stimulated alone. However, eMSC EXOs did not suppress stimulated human peripheral blood mononuclear cell proliferation, but significantly reduced secretion of 13 pro-inflammatory molecules compared to stimulated alone. In parallel, two anti-inflammatory proteins, IL-10 and IL-13, showed higher secretion, especially upon CD146+ eMSC EXO exposure. Our study suggests that eMSC, and even more, the CD146+ subpopulation, possess exosomal secretomes with strong immunomodulatory miRNA attributes. The resulting evidence could serve as a foundation for eMSC EXO-based therapeutics for the resolution of detrimental aspects of tissue inflammation.
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DOI：
10.3390/bioengineering8110166
发表时间：
2021-10-29
期刊：
Bioengineering (Basel, Switzerland)
影响因子：
--
作者：
Kouroupis D;Best TM;Kaplan LD;Correa D;Griswold AJ
通讯作者：
Griswold AJ
影响因子：
23.9
作者：
Caplan AI;Correa D
通讯作者：
Correa D
DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
影响因子：
4.6
作者：
Kouroupis D;Kaplan LD;Best TM
通讯作者：
Best TM
影响因子：
8.2
作者：
Gargett, Caroline E.;Nguyen, Hong P. T.;Ye, Louie
通讯作者：
Ye, Louie