Kidney fibrosis is the hallmark of chronic kidney disease progression; however, at present no antifibrotic therapies exist 1 – 3 . The origin, functional heterogeneity and regulation of scar-forming cells that occur during human kidney fibrosis remain poorly understood 1 , 2 , 4 . Here, using single-cell RNA sequencing, we profiled the transcriptomes of cells from the proximal and non-proximal tubules of healthy and fibrotic human kidneys to map the entire human kidney. This analysis enabled us to map all matrix-producing cells at high resolution, and to identify distinct subpopulations of pericytes and fibroblasts as the main cellular sources of scar-forming myofibroblasts during human kidney fibrosis. We used genetic fate-tracing, time-course single-cell RNA sequencing and ATAC–seq (assay for transposase-accessible chromatin using sequencing) experiments in mice, and spatial transcriptomics in human kidney fibrosis, to shed light on the cellular origins and differentiation of human kidney myofibroblasts and their precursors at high resolution. Finally, we used this strategy to detect potential therapeutic targets, and identified NKD2 as a myofibroblast-specific target in human kidney fibrosis. A range of techniques are used to investigate the molecular landscape of chronic kidney disease, and the results suggest that distinct populations of pericytes and fibroblasts are the main source of myofibroblasts in kidney fibrosis.

中文翻译：

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解码人肾纤维化中的肌成纤维细胞起源

肾纤维化是慢性肾病进展的标志；然而，目前不存在抗纤维化疗法 1 – 3 。人类肾脏纤维化期间发生的疤痕形成细胞的起源、功能异质性和调节仍然知之甚少 1, 2, 4 。在这里，我们使用单细胞 RNA 测序分析了来自健康和纤维化人类肾脏的近端和非近端小管的细胞的转录组，以绘制整个人类肾脏的图谱。该分析使我们能够以高分辨率绘制所有产生基质的细胞，并确定不同的周细胞和成纤维细胞亚群作为人类肾纤维化过程中形成疤痕的肌成纤维细胞的主要细胞来源。我们使用基因命运追踪，在小鼠中进行时程单细胞 RNA 测序和 ATAC–seq（使用测序分析转座酶可及染色质）实验，以及人肾纤维化的空间转录组学，以阐明人肾肌成纤维细胞及其前体的细胞起源和分化在高分辨率。最后，我们使用这种策略来检测潜在的治疗靶点，并将 NKD2 鉴定为人肾纤维化中的肌成纤维细胞特异性靶点。一系列技术用于研究慢性肾病的分子景观，结果表明不同的周细胞和成纤维细胞群是肾纤维化中肌成纤维细胞的主要来源。以高分辨率阐明人肾肌成纤维细胞及其前体的细胞起源和分化。最后，我们使用这种策略来检测潜在的治疗靶点，并将 NKD2 鉴定为人肾纤维化中的肌成纤维细胞特异性靶点。一系列技术用于研究慢性肾病的分子景观，结果表明不同的周细胞和成纤维细胞群是肾纤维化中肌成纤维细胞的主要来源。以高分辨率阐明人肾肌成纤维细胞及其前体的细胞起源和分化。最后，我们使用这种策略来检测潜在的治疗靶点，并将 NKD2 鉴定为人肾纤维化中的肌成纤维细胞特异性靶点。一系列技术用于研究慢性肾病的分子景观，结果表明不同的周细胞和成纤维细胞群是肾纤维化中肌成纤维细胞的主要来源。