Bruker Spatial Biology, Seattle, WA 98109, USA.
Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA.
Sci Transl Med. 2024 Nov 27;16(775):eadl1666. doi: 10.1126/scitranslmed.adl1666.
Children with systemic lupus erythematosus (SLE) are at increased risk of developing kidney disease, termed childhood-onset lupus nephritis (cLN). Single-cell transcriptomics of dissociated kidney tissue has advanced our understanding of LN pathogenesis, but loss of spatial resolution prevents interrogation of in situ cellular interactions. Using a technical advance in spatial transcriptomics, we generated a spatially resolved, single-cell resolution atlas of kidney tissue from eight patients with cLN and four control individuals. Annotated cells were assigned to 30 reference cell types, including major kidney subsets and infiltrating immune cells. Analysis of spatial distribution demonstrated that individual immune lineages localized to specific regions in cLN kidneys, including myeloid cells that trafficked to inflamed glomeruli and B cells that clustered within tubulointerstitial immune hotspots. Gene expression varied as a function of tissue location, demonstrating how incorporation of spatial data can provide new insights into the immunopathogenesis of SLE. Alterations in immune phenotypes were accompanied by parallel changes in gene expression by resident kidney stromal cells. However, there was little correlation between histologic scoring of cLN disease activity and glomerular cell transcriptional signatures at the level of individual glomeruli. Last, we identified modules of spatially correlated gene expression with predicted roles in induction of inflammation and the development of tubulointerstitial fibrosis. Single-cell spatial transcriptomics allowed insights into the molecular heterogeneity of cLN, paving the way toward more targeted and personalized treatment approaches.
患有系统性红斑狼疮 (SLE) 的儿童患肾脏疾病的风险增加，这种疾病被称为儿童发病的狼疮性肾炎 (cLN)。分离肾组织的单细胞转录组学研究提高了我们对 LN 发病机制的认识，但空间分辨率的丧失阻止了对原位细胞相互作用的研究。我们利用空间转录组学的一项技术进步，从八名 cLN 患者和四名对照个体的肾脏组织中生成了一个具有空间分辨率的单细胞分辨率图谱。注释细胞被分配到 30 个参考细胞类型，包括主要的肾脏亚群和浸润免疫细胞。空间分布分析表明，单个免疫谱系定位于 cLN 肾脏的特定区域，包括迁移到炎症性肾小球的髓样细胞和聚集在肾小管间质免疫热点的 B 细胞。基因表达随组织位置的变化而变化，证明了如何将空间数据纳入可以提供对 SLE 免疫发病机制的新见解。免疫表型的改变伴随着肾脏基质细胞基因表达的平行变化。然而，在单个肾小球水平上，cLN 疾病活动的组织学评分与肾小球细胞转录特征之间几乎没有相关性。最后，我们确定了具有预测炎症诱导和肾小管间质纤维化发展作用的空间相关基因表达模块。单细胞空间转录组学使我们能够深入了解 cLN 的分子异质性，为更有针对性和个性化的治疗方法铺平了道路。
