The cellular response to extracellular vesicles is dependent on their cell source and dose

<p><span class="TextRun SCXW24798733 BCX0"><span class="NormalTextRun SCXW24798733 BCX0">Extracellular </span><span class="NormalTextRun SCXW24798733 BCX0">vesicles</span> <span class="NormalTextRun SCXW24798733 BCX0">(EV) </span><span class="NormalTextRun SCXW24798733 BCX0">have been </span><span class="NormalTextRun SCXW24798733 BCX0">established</span><span class="NormalTextRun SCXW24798733 BCX0"> to play important roles in cell-cell communication and have </span><span class="NormalTextRun SCXW24798733 BCX0">shown promise as therapeutic agents</span><span class="NormalTextRun SCXW24798733 BCX0">.</span><span class="NormalTextRun SCXW24798733 BCX0"> However</span><span class="NormalTextRun SCXW24798733 BCX0">, </span></span><span class="TextRun SCXW24798733 BCX0"><span class="NormalTextRun SCXW24798733 BCX0">we still lack a</span><span class="NormalTextRun SCXW24798733 BCX0"> basic</span><span class="NormalTextRun SCXW24798733 BCX0"> understanding of</span></span><span class="TextRun SCXW24798733 BCX0"> <span class="NormalTextRun SCXW24798733 BCX0">how cells respond </span><span class="NormalTextRun SCXW24798733 BCX0">upon exposure to </span><span class="NormalTextRun SCXW24798733 BCX0">EVs from different cell sources at </span></span><span class="TextRun SCXW24798733 BCX0"><span class="NormalTextRun SCXW24798733 BCX0">var</span><span class="NormalTextRun SCXW24798733 BCX0">ious</span> </span><span class="TextRun SCXW24798733 BCX0"><span class="NormalTextRun SCXW24798733 BCX0">doses. </span><span class="NormalTextRun SCXW24798733 BCX0">Thus</span><span class="NormalTextRun SCXW24798733 BCX0">, </span><span class="NormalTextRun SCXW24798733 BCX0">we treated fibroblasts with EVs from twelve different cell </span><span class="NormalTextRun SCXW24798733 BCX0">sourc</span><span class="NormalTextRun SCXW24798733 BCX0">es at doses between </span><span class="NormalTextRun SCXW24798733 BCX0">2</span><span class="NormalTextRun SCXW24798733 BCX0">0</span><span class="NormalTextRun SCXW24798733 BCX0"> and </span><span class="NormalTextRun SCXW24798733 BCX0">2</span><span class="NormalTextRun SCXW24798733 BCX0">00,000 per cell, </span><span class="NormalTextRun SCXW24798733 BCX0">a</span><span class="NormalTextRun SCXW24798733 BCX0">nalyzed </span><span class="NormalTextRun SCXW24798733 BCX0">their transcript</span><span class="NormalTextRun SCXW24798733 BCX0">i</span><span class="NormalTextRun SCXW24798733 BCX0">onal effects, </span><span class="NormalTextRun SCXW24798733 BCX0">and functionally confirmed the findings</span></span><span class="TextRun SCXW24798733 BCX0"><span class="NormalTextRun SCXW24798733 BCX0"> in various cell types</span><span class="NormalTextRun SCXW24798733 BCX0"> <em>in vitro</em></span><span class="NormalTextRun SCXW24798733 BCX0">,</span><span class="NormalTextRun SCXW24798733 BCX0"> and <em>in vivo</em> using single-cell RNA-sequencing</span></span><span class="TextRun SCXW24798733 BCX0"><span class="NormalTextRun SCXW24798733 BCX0">. </span><span class="NormalTextRun SCXW24798733 BCX0">Unbiased g</span><span class="NormalTextRun SCXW24798733 BCX0">lobal</span><span class="NormalTextRun SCXW24798733 BCX0"> analysis revealed EV dose to have </span><span class="NormalTextRun SCXW24798733 BCX0">a more significant effect than cell source, </span><span class="NormalTextRun SCXW24798733 BCX0">such that </span><span class="NormalTextRun SCXW24798733 BCX0">high doses downregulat</span><span class="NormalTextRun SCXW24798733 BCX0">ed</span><span class="NormalTextRun SCXW24798733 BCX0"> exocytosis and upregulat</span><span class="NormalTextRun SCXW24798733 BCX0">ed</span> <span class="NormalTextRun SCXW24798733 BCX0">lysozomal</span><span class="NormalTextRun SCXW24798733 BCX0"> act</span><span class="NormalTextRun SCXW24798733 BCX0">ivity. </span><span class="NormalTextRun SCXW24798733 BCX0">However, </span><span class="NormalTextRun SCXW24798733 BCX0">EV cell source-specific responses were </span><span class="NormalTextRun SCXW24798733 BCX0">observed</span><span class="NormalTextRun SCXW24798733 BCX0"> at low doses</span><span class="NormalTextRun SCXW24798733 BCX0">,</span><span class="NormalTextRun SCXW24798733 BCX0"> and </span><span class="NormalTextRun SCXW24798733 BCX0">these </span><span class="NormalTextRun SCXW24798733 BCX0">reflected the </span><span class="NormalTextRun SCXW24798733 BCX0">activities </span><span class="NormalTextRun SCXW24798733 BCX0">of the</span><span class="NormalTextRun SCXW24798733 BCX0"> EV</span><span class="NormalTextRun SCXW24798733 BCX0">'</span><span class="NormalTextRun SCXW24798733 BCX0">s</span><span class="NormalTextRun SCXW24798733 BCX0"> source cell</span><span class="NormalTextRun SCXW24798733 BCX0">s</span><span class="NormalTextRun SCXW24798733 BCX0">. </span><span class="NormalTextRun SCXW24798733 BCX0">Finally, </span><span class="NormalTextRun SCXW24798733 BCX0">we </span></span><span class="TextRun SCXW24798733 BCX0"><span class="NormalTextRun SCXW24798733 BCX0">assess</span><span class="NormalTextRun SCXW24798733 BCX0">ed</span></span><span class="TextRun SCXW24798733 BCX0"><span class="NormalTextRun SCXW24798733 BCX0"> EV</span></span><span class="TextRun SCXW24798733 BCX0"><span class="NormalTextRun SCXW24798733 BCX0">-derived</span></span><span class="TextRun SCXW24798733 BCX0"><span class="NormalTextRun SCXW24798733 BCX0"> transcript abundance </span><span class="NormalTextRun SCXW24798733 BCX0">and foun</span><span class="NormalTextRun SCXW24798733 BCX0">d that immune cell</span><span class="NormalTextRun SCXW24798733 BCX0">-derived</span><span class="NormalTextRun SCXW24798733 BCX0"> EVs were </span><span class="NormalTextRun SCXW24798733 BCX0">most </span></span><span class="TextRun SCXW24798733 BCX0"><span class="NormalTextRun SCXW24798733 BCX0">associated with</span> <span class="NormalTextRun SCXW24798733 BCX0">recipient</span><span class="NormalTextRun SCXW24798733 BCX0"> cells</span></span><span class="TextRun SCXW24798733 BCX0"><span class="NormalTextRun SCXW24798733 BCX0">. </span><span class="NormalTextRun SCXW24798733 BCX0">Together, t</span><span class="NormalTextRun SCXW24798733 BCX0">his study </span><span class="NormalTextRun SCXW24798733 BCX0">provides</span><span class="NormalTextRun SCXW24798733 BCX0"> important insight into the </span><span class="NormalTextRun SCXW24798733 BCX0">cellular response to EVs.</span></span></p>