综合空间多组学分析揭示狼疮性肾炎中VCAM1+近端小管细胞的调控机制。

IF 20.6 1区 医学 Q1 RHEUMATOLOGY
Junyu Wang, Ao Zheng, Nianping Liu, Zhen Tan, Yu Shi, Tianyi Ma, Songwen Luo, Lin Zhu, Zhou Zhou, Feifei Yuan, Tiekun Li, Yuyan Gong, Jingwen Fang, Lu Liu, Xuejun Zhang, Sang-Cheol Bae, Chikashi Terao, Zhu Chen, Xiaomei Li, Guosheng Wang, Kun Qu, Chuang Guo
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引用次数: 0

摘要

目的:狼疮肾炎(LN)是系统性红斑狼疮(SLE)的严重并发症,以肾脏炎症、肾小管损伤和间质纤维化为特征。然而,这些异质细胞群的空间组织及其在LN中的调节机制仍然知之甚少。本研究的目的是研究LN中区域特异性肾脏病变和肾小管损伤的调节机制。方法:我们对LN患者和对照组的肾活检样本进行了单细胞多组和空间转录组分析,整合了迄今为止最大的东亚SLE全基因组关联研究(GWAS)(208,370个样本)的数据。验证实验采用多重免疫组织化学(mIHC)、体外慢病毒介导的转录因子过表达和功能刺激试验进行。结果:我们鉴定了表达vcam1的近端小管(PT_VCAM1)细胞是位于肾皮质的ln特异性炎症生态位(生态位5)的组成部分。硅和体外实验表明,PT_VCAM1细胞与肌成纤维细胞和免疫细胞之间的相互作用促进了它们的上皮-间质转化。轨迹分析表明,PT_VCAM1细胞起源于近端小管细胞的修复失败通路,受涉及BACH2的转录网络调节。综合GWAS分析进一步将sli相关风险单核苷酸多态性与PT_VCAM1细胞特有的顺式调控元件联系起来,包括BMP2K位点远端增强子内的单核苷酸多态性,这建立了BACH2基序。结论:总的来说,我们的研究结果将PT_VCAM1细胞描述为损伤反应性细胞状态,有助于LN的炎症和纤维化生态位,将遗传易感性与细胞损伤和疾病进展联系起来。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Integrative spatial multiomics analysis reveals regulatory mechanisms of VCAM1+ proximal tubule cells in lupus nephritis.

Objectives: Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE), characterised by kidney inflammation, tubular injury, and interstitial fibrosis. However, the spatial organisation of these heterogeneous cell populations and their regulatory mechanisms in LN remain poorly understood. The objective of this study was to investigate the regulatory mechanisms underlying region-specific kidney lesions and tubular damage in LN.

Methods: We performed single-cell multiome and spatial transcriptomic analyses on kidney biopsy samples from patients with LN and controls, integrating data from the largest East Asian SLE genome-wide association studies (GWAS) (208,370 samples) to date. Validation experiments were performed using multiplex immunohistochemistry (mIHC), in vitro lentiviral-mediated transcription factor overexpression, and functional stimulation assays.

Results: We identified VCAM1-expressing proximal tubule (PT_VCAM1) cells as components of an LN-specific inflammatory niche (niche 5) localised in the kidney cortex. Both in silico and in vitro experiments demonstrated that interactions between PT_VCAM1 cells and myofibroblasts, as well as immune cells in niche 5, promote their epithelial-mesenchymal transition. Trajectory analysis suggested that PT_VCAM1 cells originate from a failed-repair pathway in proximal tubule cells, regulated by transcriptional networks involving BACH2. Integrative GWAS analysis further linked SLE-associated risk single-nucleotide polymorphisms to cis-regulatory elements specific to PT_VCAM1 cells, including single-nucleotide polymorphisms within the distal enhancer of the BMP2K locus, which establishes a BACH2 motif.

Conclusions: Collectively, our findings characterise PT_VCAM1 cells as injury-responsive cell states that contribute to the inflammatory and fibrotic niche in LN, linking genetic predisposition to cellular injury and disease progression.

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来源期刊
Annals of the Rheumatic Diseases
Annals of the Rheumatic Diseases 医学-风湿病学
CiteScore
35.00
自引率
9.90%
发文量
3728
审稿时长
1.4 months
期刊介绍: Annals of the Rheumatic Diseases (ARD) is an international peer-reviewed journal covering all aspects of rheumatology, which includes the full spectrum of musculoskeletal conditions, arthritic disease, and connective tissue disorders. ARD publishes basic, clinical, and translational scientific research, including the most important recommendations for the management of various conditions.
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