Extracellular Vesicles from Wharton's Jelly Mesenchymal Stem Cells Suppress CD4 Expressing T Cells Through Transforming Growth Factor Beta and Adenosine Signaling in a Canine Model
Extracellular Vesicles from Wharton's Jelly Mesenchymal Stem Cells Suppress CD4 Expressing T Cells Through Transforming Growth Factor Beta and Adenosine Signaling in a Canine Model
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DOI：
10.1089/scd.2018.0097
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发表时间：
2019-02-01
影响因子：
4
通讯作者：
Hoffman, Andrew M.
中科院分区：
文献类型：
--
作者：
Crain, Sarah K.;Robinson, Sally R.;Hoffman, Andrew M.
间充质干细胞（MSC）由于其强大的免疫调节能力而被广泛研究作为潜在的治疗剂。尽管 MSC 作用于免疫细胞的具体机制正在出现，但仍然存在许多问题，包括细胞外囊泡 (EV) 介导生物活性的潜力。犬间充质干细胞对于兽医和比较疾病模型都很感兴趣，并且已被证明可以抑制 CD4(pos) T 细胞增殖。本研究的目的是确定从犬 Wharton 果冻源性 MSC (WJ-MSC EV) 中分离的 EV 是否利用先前归因于可溶性介质 [转化生长因子 β (TGF-β) 和腺苷] 的生化机制抑制 CD4(pos) T 细胞增殖。 WJ-MSC EV 的模式为 125 nm 直径、低浮力密度 (1.1 g/mL)，并表达 EV 蛋白 Alix 和 TSG101。从功能上讲，EV 以剂量依赖性方式抑制 CD4(pos) T 细胞增殖，而 EV 耗尽的样本和来自非 MSC 成纤维细胞的 EV 则不存在这种情况。 EV 对 CD4(pos) T 细胞增殖的抑制可通过 TGF-β RI 拮抗剂、中和 TGF-β 抗体或 A2A 腺苷受体阻断来抑制。 TGF-β 作为潜在复合物存在于 EV 上，很可能通过 β 聚糖与 EV 膜结合。这些数据表明，犬 WJ-MSC EV 利用 TGF-β 和腺苷信号传导来抑制 CD4(pos) T 细胞的增殖，并将有助于进一步研究免疫细胞调节机制，以及改进 WJ-MSC 及其 EV 的治疗应用。
Mesenchymal stem cells (MSCs) are widely investigated as potential therapeutic agents due to their potent immunomodulatory capacity. Although specific mechanisms by which MSC acts on immune cells are emerging, many questions remain, including the potential of extracellular vesicles (EVs) to mediate biological activities. Canine MSCs are of interest for both veterinary and comparative models of disease and have been shown to suppress CD4(pos) T cell proliferation. The aim of this study was to determine whether EV isolated from canine Wharton's jelly-derived MSC (WJ-MSC EV) suppresses CD4(pos) T cell proliferation using biochemical mechanisms previously ascribed to soluble mediators [transforming growth factor beta (TGF-beta) and adenosine]. WJ-MSC EV exhibited mode of 125 nm diameter, low buoyant density (1.1 g/mL), and expression of EV proteins Alix and TSG101. Functionally, EVs inhibited CD4(pos) T cell proliferation in a dose-dependent manner, which was absent in EV-depleted samples and EVs from non-MSC fibroblasts. EV suppression of CD4(pos) T cell proliferation was inhibited by a TGF-beta RI antagonist, neutralizing antibodies to TGF-beta, or A2A adenosine receptor blockade. TGF-beta was present on EVs as latent complexes most likely tethered to EV membrane by betaglycan. These data demonstrate that canine WJ-MSC EV utilizes TGF-beta and adenosine signaling to suppress proliferation of CD4(pos) T cell and will enable further investigation into mechanisms of immune cell modulation, as well as refinement of WJ-MSC and their EVs for therapeutic application.