Department of Chemical Engineering, Stanford University, Stanford, CA, United States.
Sarafan ChEM-H, Stanford University, Stanford, CA, United States.
Clin Chem. 2024 Nov 4;70(11):1344-1354. doi: 10.1093/clinchem/hvae137.
Early detection of the cell type changes underlying several genitourinary tract diseases largely remains an unmet clinical need, where existing assays, if available, lack the cellular resolution afforded by an invasive biopsy. While messenger RNA in urine could reflect the dynamic signal that facilitates early detection, current measurements primarily detect single genes and thus do not reflect the entire transcriptome and the underlying contributions of cell type-specific RNA.
We isolated and sequenced the cell-free RNA (cfRNA) and sediment RNA from human urine samples (n = 6 healthy controls and n = 12 kidney stone patients) and measured the urine metabolome. We analyzed the resulting urine transcriptomes by deconvolving the noninvasively measurable cell type contributions and comparing to plasma cfRNA and the measured urine metabolome.
Urine transcriptome cell type deconvolution primarily yielded relative fractional contributions from genitourinary tract cell types in addition to cell types from high-turnover solid tissues beyond the genitourinary tract. Comparison to plasma cfRNA yielded enrichment of metabolic pathways and a distinct cell type spectrum. Integration of urine transcriptomic and metabolomic measurements yielded enrichment for metabolic pathways involved in amino acid metabolism and overlapped with metabolic subsystems associated with proximal tubule function.
Noninvasive whole transcriptome measurements of human urine cfRNA and sediment RNA reflects signal from hard-to-biopsy tissues exhibiting low representation in blood plasma cfRNA liquid biopsy at cell type resolution and are enriched in signal from metabolic pathways measurable in the urine metabolome.
早期检测几种泌尿道疾病相关的细胞类型变化在很大程度上仍是未满足的临床需求，而现有的检测方法（如果有的话）缺乏侵入性活检所提供的细胞分辨率。虽然尿液中的信使 RNA 可以反映促进早期检测的动态信号，但目前的测量方法主要检测单个基因，因此无法反映整个转录组以及特定细胞类型 RNA 的潜在贡献。
我们从人类尿液样本（n=6 名健康对照和 n=12 名肾结石患者）中分离和测序了细胞游离 RNA（cfRNA）和沉淀物 RNA，并测量了尿液代谢组。我们通过推断可无创测量的细胞类型贡献来分析由此产生的尿液转录组，并将其与血浆 cfRNA 和测量的尿液代谢组进行比较。
尿液转录组细胞类型去卷积主要产生了来自泌尿道细胞类型的相对分数贡献，以及来自泌尿道以外高周转率实体组织的细胞类型。与血浆 cfRNA 的比较产生了代谢途径的富集和独特的细胞类型谱。尿液转录组和代谢组学测量的整合产生了与氨基酸代谢相关的代谢途径的富集，并与与近端肾小管功能相关的代谢子系统重叠。
无创的人类尿液 cfRNA 和沉淀物 RNA 全转录组测量反映了来自难以活检组织的信号，这些组织在血液血浆 cfRNA 液体活检中的代表性较低，在细胞类型分辨率下，并且在尿液代谢组中可测量的代谢途径信号中富集。
