Single-Cell Transcriptome Profiling of the Kidney Glomerulus Identifies Key Cell Types and Reactions to Injury
Single-Cell Transcriptome Profiling of the Kidney Glomerulus Identifies Key Cell Types and Reactions to Injury
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DOI：
10.1681/asn.2020020220
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发表时间：
2020-10-01
影响因子：
13.6
通讯作者：
Shaw, Andrey S.
中科院分区：
文献类型：
--
作者：
Chung, Jun-Jae;Goldstein, Leonard;Shaw, Andrey S.
背景肾小球是一种特殊的毛细血管床，参与尿液的产生和血压的控制。肾小球损伤是慢性肾脏病的主要原因，慢性肾脏病是一种流行病，没有治疗选择。单细胞转录学从根本上提高了我们描述复杂器官的能力，比如肾脏。然而，在以往的单细胞肾脏研究中，由于肾小球细胞的稀少和难治性，肾小球细胞在很大程度上被低估了。方法采用单细胞RNA测序的方法，综合分析了健康小鼠和四种不同疾病模型(肾毒血清肾炎、糖尿病、阿霉素中毒和CD2AP缺乏症)肾小球中的细胞类型。鉴定了系膜细胞、传入和传出小动脉的血管平滑肌细胞、壁上皮细胞和三种类型的内皮细胞的新的标记基因和基因特征。对疾病模型的分析揭示了肾小球中特定细胞类型和特定损伤类型的反应，包括肾毒性免疫损伤后足细胞中河马通路的急性激活。YAP或TAZ的条件性缺失会导致损伤后更严重和更持久的蛋白尿，以及更严重的肾小球硬化。结论从健康和损伤小鼠中获得全面的高分辨率、单细胞转录图谱，为识别新的疾病相关基因和途径提供了资源。
Background The glomerulus is a specialized capillary bed that is involved in urine production and BP control. Glomerular injury is a major cause of CKD, which is epidemic and without therapeutic options. Single-cell transcriptomics has radically improved our ability to characterize complex organs, such as the kidney. Cells of the glomerulus, however, have been largely underrepresented in previous single-cell kidney studies due to their paucity and intractability.Methods Single-cell RNA sequencing comprehensively characterized the types of cells in the glomerulus from healthy mice and from four different disease models (nephrotoxic serum nephritis, diabetes, doxorubicin toxicity, and CD2AP deficiency).Results All cell types in the glomerulus were identified using unsupervised clustering analysis. Novel marker genes and gene signatures of mesangial cells, vascular smooth muscle cells of the afferent and efferent arterioles, parietal epithelial cells, and three types of endothelial cells were identified. Analysis of the disease models revealed cell type-specific and injury type-specific responses in the glomerulus, including acute activation of the Hippo pathway in podocytes after nephrotoxic immune injury. Conditional deletion of YAP or TAZ resulted in more severe and prolonged proteinuria in response to injury, as well as worse glomerulosclerosis.Conclusions Generation of comprehensive high-resolution, single-cell transcriptomic profiles of the glomerulus from healthy and injured mice provides resources to identify novel disease-related genes and pathways.