Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge and Karolinska Comprehensive Cancer Center, Stockholm, Sweden.
Sci Adv. 2023 Sep;9(35):eadh1168. doi: 10.1126/sciadv.adh1168. Epub 2023 Sep 1.
Extracellular vesicles (EVs) have been established to play important roles in cell-cell communication and shown promise as therapeutic agents. However, we still lack a basic understanding of how cells respond upon exposure to EVs from different cell sources at various doses. Thus, we treated fibroblasts with EVs from 12 different cell sources at doses between 20 and 200,000 per cell, analyzed their transcriptional effects, and functionally confirmed the findings in various cell types in vitro, and in vivo using single-cell RNA sequencing. Unbiased global analysis revealed EV dose to have a more significant effect than cell source, such that high doses down-regulated exocytosis and up-regulated lysosomal activity. However, EV cell source-specific responses were observed at low doses, and these reflected the activities of the EV's source cells. Last, we assessed EV-derived transcript abundance and found that immune cell-derived EVs were most associated with recipient cells. Together, this study provides important insights into the cellular response to EVs.
细胞外囊泡 (EVs) 在细胞间通讯中发挥着重要作用，并有望成为治疗药物。然而，我们仍然缺乏基本的了解，即当细胞暴露于来自不同细胞源的 EV 时，细胞会如何反应，以及在不同剂量下会如何反应。因此，我们用来自 12 种不同细胞源的 EV 处理成纤维细胞，剂量范围为每个细胞 20 到 200,000 个，分析它们的转录效应，并在体外的各种细胞类型中进行功能验证，以及使用单细胞 RNA 测序进行体内验证。无偏倚的全局分析表明，EV 剂量比细胞源的影响更大，高剂量会下调胞吐作用，上调溶酶体活性。然而，在低剂量下观察到 EV 细胞源特异性反应，这些反应反映了 EV 来源细胞的活性。最后，我们评估了 EV 衍生的转录本丰度，发现免疫细胞来源的 EV 与受体细胞最相关。总之，这项研究为细胞对 EV 的反应提供了重要的见解。
