SnRNA sequencing defines signaling by RBC-derived extracellular vesicles in the murine heart

Extracellular vesicles (EVs) mediate intercellular signaling by
transferring their cargo to recipient cells, but the functional
consequences of signaling are not fully appreciated. Red blood cell
(RBC)-derived EVs are abundant in circulation and have been implicated in
regulating immune responses. Here, we use a transgenic mouse model for
fluorescence-based mapping of RBC-EV recipient cells to assess the role of
this intercellular signaling mechanism in heart disease. Using
fluorescent-based mapping, we detected an increase in RBC-EV-targeted
cardiomyocytes in a murine model of ischemic heart failure. Single cell
nuclear RNA sequencing of the heart revealed a complex landscape of
cardiac cells targeted by RBC-EVs, with enrichment of genes implicated in
cell proliferation and stress signaling pathways compared to non-targeted
cells. Correspondingly, cardiomyocytes targeted by RBC-EVs more frequently
express cellular markers of DNA synthesis, suggesting the functional
significance of EV-mediated signaling. In conclusion, our mouse model for
mapping of EV-recipient cells reveals a complex cellular network of RBC-EV
mediated intercellular communication in ischemic heart failure and
suggests a functional role for this mode of intercellular signaling.

细胞外囊泡（EVs）通过向受体细胞转运其货物分子介导细胞间信号传导，但其信号传导的功能后果尚未得到充分认识。红细胞（RBC）来源的EVs在循环中含量丰富，并被认为参与免疫应答的调节。本研究中，我们采用基于荧光标记的红细胞EV受体细胞示踪转基因小鼠模型，以评估该细胞间信号传导机制在心脏疾病中的作用。通过荧光示踪技术，我们在缺血性心力衰竭小鼠模型中检测到靶向红细胞EV的心肌细胞数量增加。心脏的单细胞核RNA测序揭示了红细胞EV靶向的心脏细胞的复杂图谱，与非靶向细胞相比，这些细胞中参与细胞增殖和应激信号通路的基因显著富集。相应地，红细胞EV靶向的心肌细胞更频繁地表达DNA合成的细胞标志物，提示EV介导的信号传导具有功能意义。综上，我们建立的EV受体细胞示踪小鼠模型揭示了缺血性心力衰竭中红细胞EV介导的细胞间通讯的复杂细胞网络，并提示这种细胞间信号传导模式具有功能性作用。