美国华盛顿大学Benjamin D. Humphreys课题组在研究中取得进展。他们利用转录组学、表观基因组学和空间代谢组学细胞剖析，揭示了人类肾脏的区域解剖结构。相关论文发表在2024年3月20日出版的《细胞-代谢》杂志上。

研究人员采用高通量单细胞ATAC/RNA测序（SHARE-seq）和空间分辨代谢组学方法，对来自不同肾脏解剖区域的54份人体样本进行了分析。研究生成了446267个细胞的转录组图谱和401875个细胞的染色质可及性图谱，并开发了一个软件包来分析408218个空间解析代谢组。

研究发现，同一类型的细胞，包括薄肢细胞、亨列升支粗环细胞和主细胞，会因解剖位置的不同而显示出不同的转录组、染色质可及性和代谢组特征。对代谢相关基因图谱的研究表明肾小管节段之间的代谢特征并不重叠，患者来源的近端肾小管（PT）细胞脂质代谢紊乱。

将多模态全息图学与临床数据相结合，研究人员发现PLEKHA1是一种疾病标志物，体外敲除PLEKHA1可增加PT分化过程中的基因表达，这表明PLEKHA1可能具有致病作用。这项研究揭示了之前未知的以人类肾脏解剖学为基础的细胞异质性。

附：英文原文

Title: Transcriptomic, epigenomic, and spatial metabolomic cell profiling redefines regional human kidney anatomy

Author: Haikuo Li, Dian Li, Nicolas Ledru, Qiao Xuanyuan, Haojia Wu, Amish Asthana, Lori N. Byers, Stefan G. Tullius, Giuseppe Orlando, Sushrut S. Waikar, Benjamin D. Humphreys

Issue&Volume: 2024-03-20

Abstract: A large-scale multimodal atlas that includes major kidney regions is lacking. Here, we employed simultaneous high-throughput single-cell ATAC/RNA sequencing (SHARE-seq) and spatially resolved metabolomics to profile 54 human samples from distinct kidney anatomical regions. We generated transcriptomes of 446,267 cells and chromatin accessibility profiles of 401,875 cells and developed a package to analyze 408,218 spatially resolved metabolomes. We find that the same cell type, including thin limb, thick ascending limb loop of Henle and principal cells, display distinct transcriptomic, chromatin accessibility, and metabolomic signatures, depending on anatomic location. Surveying metabolism-associated gene profiles revealed non-overlapping metabolic signatures between nephron segments and dysregulated lipid metabolism in diseased proximal tubule (PT) cells. Integrating multimodal omics with clinical data identified PLEKHA1 as a disease marker, and its in vitro knockdown increased gene expression in PT differentiation, suggesting possible pathogenic roles. This study highlights previously underrepresented cellular heterogeneity underlying the human kidney anatomy.

DOI: 10.1016/j.cmet.2024.02.015

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(24)00061-5