G-MDSCs promote aging-related cardiac fibrosis by activating myofibroblasts and preventing senescence.
G-MDSCs promote aging-related cardiac fibrosis by activating myofibroblasts and preventing senescence.
复制标题
G-MDSC 通过激活肌成纤维细胞和预防衰老来促进与衰老相关的心脏纤维化。
DOI：
10.1038/s41419-021-03874-7
复制
发表时间：
2021-06-08
影响因子：
9
通讯作者：
Lu L
中科院分区：
文献类型：
--
作者：
Sun SN;Ni SH;Li Y;Liu X;Deng JP;Chen ZX;Li H;Feng WJ;Huang YS;Li DN;Xian SX;Yang ZQ;Wang LJ;Lu L
衰老是心力衰竭最突出的危险因素之一。髓样衍生的抑制细胞（MDSC）积聚在老化的组织中，并已确认与各种与衰老有关的疾病有关。但是，MDSC在衰老心脏中的作用仍然未知。通过RNA-Seq和生化方法，我们发现与单核细胞MDSC（M-MDSC）相比，肉芽细胞MDSC（G-MDSC）在衰老心脏中显着积累。因此，我们探讨了G-MDSC对衰老心脏的影响。我们发现，衰老小鼠的G-MDSC的收养转移向年轻的心脏转移导致心脏舒张功能障碍通过诱导心脏纤维化，类似于衰老心脏的心脏纤维化。 S100A8/A9源自G-MDSCS诱导的炎症表型，并在成纤维细胞中提高了骨桥蛋白（OPN）水平。由G-MDSC介导的成纤维细胞中成纤维细胞生长因子2（FGF2）表达的上调促进了成纤维细胞的抗阳离子和抗凋亡表型。 SOX9是FGF2的下游基因，是FGF2介导的和G-MDSC介导的纤维化效应所必需的。有趣的是，成纤维细胞中的FGF2水平和SOX9水平都上调，但在G-MDSC中均未上调，并且与S100A8/9无关。因此，确定了调节成纤维细胞自我更新和抗凋亡表型的新型FGF2-SOX9信号轴。我们的研究揭示了G-MDSC通过S100A8/A9的分泌促进心脏纤维化的机制，以及在老化期间成纤维细胞中FGF2-SOX9信号的调节。
Aging is one of the most prominent risk factors for heart failure. Myeloid-derived suppressor cells (MDSCs) accumulate in aged tissue and have been confirmed to be associated with various aging-related diseases. However, the role of MDSCs in the aging heart remains unknown. Through RNA-seq and biochemical approaches, we found that granulocytic MDSCs (G-MDSCs) accumulated significantly in the aging heart compared with monocytic MDSCs (M-MDSCs). Therefore, we explored the effects of G-MDSCs on the aging heart. We found that the adoptive transfer of G-MDSCs of aging mice to young hearts resulted in cardiac diastolic dysfunction by inducing cardiac fibrosis, similar to that in aging hearts. S100A8/A9 derived from G-MDSCs induced inflammatory phenotypes and increased the osteopontin (OPN) level in fibroblasts. The upregulation of fibroblast growth factor 2 (FGF2) expression in fibroblasts mediated by G-MDSCs promoted antisenescence and antiapoptotic phenotypes of fibroblasts. SOX9 is the downstream gene of FGF2 and is required for FGF2-mediated and G-MDSC-mediated profibrotic effects. Interestingly, both FGF2 levels and SOX9 levels were upregulated in fibroblasts but not in G-MDSCs and were independent of S100A8/9. Therefore, a novel FGF2-SOX9 signaling axis that regulates fibroblast self-renewal and antiapoptotic phenotypes was identified. Our study revealed the mechanism by which G-MDSCs promote cardiac fibrosis via the secretion of S100A8/A9 and the regulation of FGF2-SOX9 signaling in fibroblasts during aging.
登录
查看更多内容
影响因子：
10.1
作者：
Gabrilovich DI
通讯作者：
Gabrilovich DI
影响因子：
8.7
作者：
Goh C;Narayanan S;Hahn YS
通讯作者：
Hahn YS
影响因子：
13
作者：
Magnussen, Christina;Niiranen, Teemu J.;Schnabel, Renate B.
通讯作者：
Schnabel, Renate B.
影响因子：
37.8
作者：
Lacraz, Gregory P. A.;Junker, Jan Philipp;Van Rooij, Eva
通讯作者：
Van Rooij, Eva
影响因子：
20.1
作者：
Loffredo FS;Nikolova AP;Pancoast JR;Lee RT
通讯作者：
Lee RT