Single-cell analysis identifies distinct macrophage phenotypes associated with pro-disease and pro-resolving functions in the endometriotic niche
Single-cell analysis identifies distinct macrophage phenotypes associated with pro-disease and pro-resolving functions in the endometriotic niche
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单细胞分析鉴定了与子宫内膜异位生态位中促疾病和促解决功能相关的不同巨噬细胞表型
DOI：
10.1101/2024.03.07.583861
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Henlon Y
中科院分区：
文献类型：
--
作者：
Henlon Y
子宫内膜异位症对全球1.9亿妇女的健康相关生活质量产生了负面影响。对于这种衰弱的疾病，迫切需要非激素治疗的新进展。巨噬细胞在子宫内膜异位症的病理生理过程中发挥着重要作用，是一种很有前途的治疗靶点。在目前的研究中，我们通过单细胞分析揭示了实验性子宫内膜异位症小鼠模型中与子宫内膜异位症相关的巨噬细胞亚群转录的全部复杂性。我们已经确定了两个关键的病变驻留群体，它们类似于i)肿瘤相关巨噬细胞(以Folr2、MRc1、Gas6和Ccl8+的表达为特征)，促进人子宫内膜间质细胞中Col1a1和Tgfb1的表达，并增加人脐静脉内皮细胞中的血管生成网；以及ii)瘢痕相关巨噬细胞(MMP12、CD9、Spp1、TREM2+)，表现出与纤维化和基质重塑相关的表型。我们还描述了一组与脂质相关的巨噬细胞表型(APOE，Saa3，Pid1)相一致的大的腹膜巨噬细胞，伴随着脂质代谢的改变和胆固醇的外流。使用APOE模拟物的功能实验的获得导致了病变大小和纤维化的减少，以及临床前模型中腹膜巨噬细胞群的改变。利用对小鼠和人类单细胞数据集的跨物种分析，我们确定了腹膜和病变驻留的巨噬细胞亚群的一致性，确定了转录表型的关键相似和不同。最终，我们预计这些发现将为特定巨噬细胞靶向治疗的设计和使用提供参考，并为子宫内膜异位症的治疗开辟广阔的道路。
Endometriosis negatively impacts the health-related quality of life of 190 million women worldwide. Novel advances in nonhormonal treatments for this debilitating condition are desperately needed. Macrophages play a vital role in the pathophysiology of endometriosis and represent a promising therapeutic target. In the current study, we revealed the full transcriptomic complexity of endometriosis-associated macrophage subpopulations using single-cell analyses in a preclinical mouse model of experimental endometriosis. We have identified two key lesion-resident populations that resemble i) tumor-associated macrophages (characterized by expression ofFolr2,Mrc1,Gas6,andCcl8+) that promoted expression ofCol1a1andTgfb1in human endometrial stromal cells and increased angiogenic meshes in human umbilical vein endothelial cells, and ii) scar-associated macrophages (Mmp12, Cd9, Spp1, Trem2+) that exhibited a phenotype associated with fibrosis and matrix remodeling. We also described a population of proresolving large peritoneal macrophages that align with a lipid-associated macrophage phenotype (Apoe, Saa3, Pid1) concomitant with altered lipid metabolism and cholesterol efflux. Gain of function experiments using an Apoe mimetic resulted in decreased lesion size and fibrosis, and modification of peritoneal macrophage populations in the preclinical model. Using cross-species analysis of mouse and human single-cell datasets, we determined the concordance of peritoneal and lesion-resident macrophage subpopulations, identifying key similarities and differences in transcriptomic phenotypes. Ultimately, we envisage that these findings will inform the design and use of specific macrophage-targeted therapies and open broad avenues for the treatment of endometriosis.
载脂蛋白 E 通过作用于抗原呈递细胞来调节免疫激活。
影响因子：
6.4
作者：
C. Tenger;Xinghua Zhou
通讯作者：
Xinghua Zhou
影响因子：
64.8
作者：
Ramachandran, P.;Dobie, R.;Henderson, N. C.
通讯作者：
Henderson, N. C.