Aging-associated changes in CD47 arrangement and interaction with thrombospondin-1 on red blood cells visualized by super-resolution imaging.,Aging Cell

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Aging-associated changes in CD47 arrangement and interaction with thrombospondin-1 on red blood cells visualized by super-resolution imaging.
Aging Cell ( IF 8.0 ) Pub Date : 2020-08-31 , DOI: 10.1111/acel.13224
Feng Wang _{1,

2} , Yan-Hou Liu _{1,

2} , Ting Zhang _{1,

2} , Jing Gao ₃ , Yangyue Xu ₃ , Guang-Yao Xie _{1,

2} , Wen-Jie Zhao _{1,

2} , Hongda Wang ₃ , Yong-Guang Yang _{1,

2,

4}

Affiliation

CD47 serves as a ligand for signaling regulatory protein α (SIRPα) and as a receptor for thrombospondin‐1 (TSP‐1). Although CD47, TSP‐1, and SIRPα are thought to be involved in the clearance of aged red blood cells (RBCs), aging‐associated changes in the expression and interaction of these molecules on RBCs have been elusive. Using direct stochastic optical reconstruction microscopy (dSTORM)‐based imaging and quantitative analysis, we can report that CD47 molecules on young RBCs reside as nanoclusters with little binding to TSP‐1, suggesting a minimal role for TSP‐1/CD47 signaling in normal RBCs. On aged RBCs, CD47 molecules decreased in number but formed bigger and denser clusters, with increased ability to bind TSP‐1. Exposure of aged RBCs to TSP‐1 resulted in a further increase in the size of CD47 clusters via a lipid raft‐dependent mechanism. Furthermore, CD47 cluster formation was dramatically inhibited on thbs1^−/− mouse RBCs and associated with a significantly prolonged RBC lifespan. These results indicate that the strength of CD47 binding to its ligand TSP‐1 is predominantly determined by the distribution pattern and not the amount of CD47 molecules on RBCs, and offer direct evidence for the role of TSP‐1 in phagocytosis of aged RBCs. This study provides clear nanoscale pictures of aging‐associated changes in CD47 distribution and TSP‐1/CD47 interaction on the cell surface, and insights into the molecular basis for how these molecules coordinate to remove aged RBCs.

中文翻译：

通过超分辨率成像可视化红细胞上 CD47 排列的衰老相关变化以及与血小板反应蛋白-1 的相互作用。

CD47 充当信号调节蛋白 α (SIRPα) 的配体和血小板反应蛋白-1 (TSP-1) 的受体。尽管 CD47、TSP-1 和 SIRPα 被认为参与了衰老红细胞 (RBC) 的清除，但这些分子在 RBC 上的表达和相互作用与衰老相关的变化一直难以捉摸。使用基于直接随机光学重建显微镜（dSTORM）的成像和定量分析，我们可以报告年轻红细胞上的 CD47 分子以纳米簇形式存在，与 TSP-1 几乎没有结合，这表明 TSP-1/CD47 信号传导在正常红细胞中的作用很小。在老化的红细胞上，CD47 分子数量减少，但形成更大、更密集的簇，结合 TSP-1 的能力增强。将老化的红细胞暴露于 TSP-1 会通过脂筏依赖性机制导致 CD47 簇的大小进一步增加。此外， Thbs1 ^-/−小鼠红细胞上的 CD47 簇形成受到显着抑制，并与红细胞寿命显着延长相关。这些结果表明，CD47与其配体TSP-1结合的强度主要取决于分布模式，而不是红细胞上CD47分子的数量，并为TSP-1在老化红细胞吞噬作用中的作用提供了直接证据。这项研究提供了细胞表面 CD47 分布和 TSP-1/CD47 相互作用的衰老相关变化的清晰纳米级图像，并深入了解这些分子如何协调去除老化红细胞的分子基础。

更新日期：2020-10-23

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