BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

中文翻译：

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人类尿液跨转录组和代谢组的去卷积。


背景 早期检测几种泌尿生殖道疾病背后的细胞类型变化在很大程度上仍然是一个未满足的临床需求，其中现有的检测方法（如果有）缺乏侵入性活检提供的细胞分辨率。虽然尿液中的信使 RNA 可以反映有助于早期检测的动态信号，但目前的测量主要检测单个基因，因此不能反映整个转录组和细胞类型特异性 RNA 的潜在贡献。方法 我们从人尿液样本 （n = 6 名健康对照者和 n = 12 名肾结石患者） 中分离和测序游离 RNA （cfRNA） 和沉淀物 RNA，并测量尿液代谢组。我们通过对无创可测量的细胞类型贡献进行反卷积，并与血浆 cfRNA 和测量的尿液代谢组进行比较，分析了得到的尿液转录组。结果 尿液转录组细胞类型反卷积主要产生泌尿生殖道细胞类型的相对分数贡献，此外还产生泌尿生殖道以外高周转实体组织的细胞类型。与血浆 cfRNA 相比，代谢途径富集和不同的细胞类型谱。尿液转录组学和代谢组学测量的整合提高了参与氨基酸代谢的代谢途径，并与近端肾小管功能相关的代谢子系统重叠。结论 人尿液 cfRNA 和沉淀物 RNA 的无创全转录组测量反映了来自难以活检的组织的信号，这些组织在血浆 cfRNA 液体活检中以细胞类型分辨率表现出低代表性，并且富含来自尿液代谢组可测量的代谢途径的信号。