{"title":"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。","authors":"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","doi":"10.1016/j.ard.2025.08.015","DOIUrl":null,"url":null,"abstract":"<p><strong>Objectives: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.6000,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Integrative spatial multiomics analysis reveals regulatory mechanisms of VCAM1<sup>+</sup> proximal tubule cells in lupus nephritis.\",\"authors\":\"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\",\"doi\":\"10.1016/j.ard.2025.08.015\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objectives: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":8087,\"journal\":{\"name\":\"Annals of the Rheumatic Diseases\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":20.6000,\"publicationDate\":\"2025-09-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of the Rheumatic Diseases\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ard.2025.08.015\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"RHEUMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of the Rheumatic Diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ard.2025.08.015","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
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.
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.