Single Cell and Spatial Transcriptomics Define a Proinflammatory and Profibrotic Niche After Kidney Injury.

IF 14.1 1区 材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Li Li, Jinlin Liao, Yuxi Zhang, Zifu Yao, Junxin Huang, Kejia Wu, Lu Li, Yiling Peng, Haili Zhu, Xue Hong, Xi Liu, Lili Zhou, Fan Fan Hou, Haiyan Fu, Youhua Liu
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Abstract

Kidney fibrosis is the common outcome of chronic kidney disease (CKD). It often instigates in the focal sites by forming the fibrogenic niche after injury. In this study, using single-cell RNA sequencing (scRNA-seq) and a spatial transcriptomic (ST) approach, the cellular heterogeneity, spatial organization, and molecular interactions are delineated in the fibrotic kidney. Through analyses of the scRNA-seq and ST data from normal and fibrotic kidneys in mice subjected to unilateral ischemia-reperfusion injury, a tenascin C (TNC)-enriched, proinflammatory, and profibrotic microenvironment is identified that facilitated macrophage activation and promoted renal inflammation and fibrosis. Both TNC-enriched decellularized kidney tissue scaffold and exogenous TNC protein promoted bone marrow-derived macrophages activation though Toll-like receptor 4 (TLR4)/NF-κB signaling. Either pharmacological inhibition of TLR4 signaling or genetic knockout of its gene alleviated renal inflammation and fibrosis by inhibiting macrophage activation in vivo. Finally, chimeric mice that received bone marrow transplantation from TLR4-deficient donors are protected against kidney inflammation and fibrosis. These results suggest that TNC plays a crucial role in orchestrating the formation of a proinflammatory and profibrotic niche that promotes renal inflammation and fibrosis by activating macrophages via TLR4/NF-κB signaling. The findings underscore the complex interplay among fibroblasts, extracellular microenvironment, and macrophages that drive kidney fibrosis.

单细胞和空间转录组学定义肾损伤后的促炎和纤维化生态位。
肾纤维化是慢性肾脏疾病(CKD)的常见结果。它通常在损伤后在病灶部位形成纤维原性生态位。在这项研究中,使用单细胞RNA测序(scRNA-seq)和空间转录组学(ST)方法,描述了纤维化肾脏中的细胞异质性、空间组织和分子相互作用。通过分析单侧缺血再灌注损伤小鼠正常肾脏和纤维化肾脏的scRNA-seq和ST数据,发现tenascin C (TNC)富集、促炎和促纤维化的微环境促进巨噬细胞活化,促进肾脏炎症和纤维化。TNC富集的脱细胞肾组织支架和外源性TNC蛋白均通过toll样受体4 (TLR4)/NF-κB信号通路促进骨髓源性巨噬细胞活化。药物抑制TLR4信号或基因敲除其基因均可通过抑制体内巨噬细胞活化来减轻肾脏炎症和纤维化。最后,接受tlr4缺陷供体骨髓移植的嵌合小鼠可以防止肾脏炎症和纤维化。这些结果表明,TNC在协调促炎和促纤维化生态位的形成中起着至关重要的作用,该生态位通过TLR4/NF-κB信号激活巨噬细胞,促进肾脏炎症和纤维化。这些发现强调了成纤维细胞、细胞外微环境和巨噬细胞之间复杂的相互作用,这些相互作用驱动肾纤维化。
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来源期刊
Advanced Science
Advanced Science CHEMISTRY, MULTIDISCIPLINARYNANOSCIENCE &-NANOSCIENCE & NANOTECHNOLOGY
CiteScore
18.90
自引率
2.60%
发文量
1602
审稿时长
1.9 months
期刊介绍: Advanced Science is a prestigious open access journal that focuses on interdisciplinary research in materials science, physics, chemistry, medical and life sciences, and engineering. The journal aims to promote cutting-edge research by employing a rigorous and impartial review process. It is committed to presenting research articles with the highest quality production standards, ensuring maximum accessibility of top scientific findings. With its vibrant and innovative publication platform, Advanced Science seeks to revolutionize the dissemination and organization of scientific knowledge.
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