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Single-cell analysis reveals immune landscape in kidneys of patients with chronic transplant rejection.

ABSTRACT: Rationale: Single-cell RNA sequencing (scRNA-seq) has provided an unbiased assessment of specific profiling of cell populations at the single-cell level. Conventional renal biopsy and bulk RNA-seq only average out the underlying differences, while the extent of chronic kidney transplant rejection (CKTR) and how it is shaped by cells and states in the kidney remain poorly characterized. Here, we analyzed cells from CKTR and matched healthy adult kidneys at single-cell resolution. Methods: High-quality transcriptomes were generated from three healthy human kidneys and two CKTR biopsies. Unsupervised clustering analysis of biopsy specimens was performed to identify fifteen distinct cell types, including major immune cells, renal cells and a few types of stromal cells. Single-sample gene set enrichment (ssGSEA) algorithm was utilized to explore functional differences between cell subpopulations and between CKTR and normal cells. Results: Natural killer T (NKT) cells formed five subclasses, representing CD4+ T cells, CD8+ T cells, cytotoxic T lymphocytes (CTLs), regulatory T cells (Tregs) and natural killer cells (NKs). Memory B cells were classified into two subtypes, representing reverse immune activation. Monocytes formed a classic CD14+ group and a nonclassical CD16+ group. We identified a novel subpopulation [myofibroblasts (MyoF)] in fibroblasts, which express collagen and extracellular matrix components. The CKTR group was characterized by increased numbers of immune cells and MyoF, leading to increased renal rejection and fibrosis. Conclusions: By assessing functional differences of subtype at single-cell resolution, we discovered different subtypes that correlated with distinct functions in CKTR. This resource provides deeper insights into CKTR biology that will be helpful in the diagnosis and treatment of CKTR.

SUBMITTER: Liu Y

PROVIDER: S-EPMC7392010 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Single-cell analysis reveals immune landscape in kidneys of patients with chronic transplant rejection.

Liu Yongguang Y Hu Jianmin J Liu Ding D Zhou Song S Liao Jun J Liao Guorong G Yang Siqiang S Guo Zefeng Z Li Yuzhu Y Li Shichao S Chen Hua H Guo Ying Y Li Ming M Fan Lipei L Li Liuyang L Lin Anqi A Zhao Ming M

Theranostics 20200711 19

<b>Rationale:</b> Single-cell RNA sequencing (scRNA-seq) has provided an unbiased assessment of specific profiling of cell populations at the single-cell level. Conventional renal biopsy and bulk RNA-seq only average out the underlying differences, while the extent of chronic kidney transplant rejection (CKTR) and how it is shaped by cells and states in the kidney remain poorly characterized. Here, we analyzed cells from CKTR and matched healthy adult kidneys at single-cell resolution. <b>Method ...[more]

PMID: 32754283

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Project description:BackgroundIschemic acute kidney injury (AKI) is a common syndrome associated with considerable mortality and healthcare costs. Up to now, the underlying pathogenesis of ischemic AKI remains incompletely understood, and specific strategies for early diagnosis and treatment of ischemic AKI are still lacking. Here, this study aimed to define the transcriptomic landscape of AKI patients through single-cell RNA sequencing (scRNA-seq) analysis in kidneys.MethodsIn this study, scRNA-seq technology was applied to kidneys from two ischemic AKI patients, and three human public scRNA-seq datasets were collected as controls. Differentially expressed genes (DEGs) and cell clusters of kidneys were determined. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, as well as the ligand-receptor interaction between cells, were performed. We also validated several DEGs expression in kidneys from human ischemic AKI and ischemia/reperfusion (I/R) injury induced AKI mice through immunohistochemistry staining.Results15 distinct cell clusters were determined in kidney from subjects of ischemic AKI and control. The injured proximal tubules (PT) displayed a proapoptotic and proinflammatory phenotype. PT cells of ischemic AKI had up-regulation of novel pro-apoptotic genes including USP47 , RASSF4 , EBAG9 , IER3 , SASH1 , SEPTIN7 , and NUB1 , which have not been reported in ischemic AKI previously. Several hub genes were validated in kidneys from human AKI and renal I/R injury mice, respectively. Furthermore, PT highly expressed DEGs enriched in endoplasmic reticulum stress, autophagy, and retinoic acid-inducible gene I (RIG-I) signaling. DEGs overexpressed in other tubular cells were primarily enriched in nucleotide-binding and oligomerization domain (NOD)-like receptor signaling, estrogen signaling, interleukin (IL)-12 signaling, and IL-17 signaling. Overexpressed genes in kidney-resident immune cells including macrophages, natural killer T (NKT) cells, monocytes, and dendritic cells were associated with leukocyte activation, chemotaxis, cell adhesion, and complement activation. In addition, the ligand-receptor interactions analysis revealed prominent communications between macrophages and monocytes with other cells in the process of ischemic AKI.ConclusionTogether, this study reveals distinct cell-specific transcriptomic atlas of kidney in ischemic AKI patients, altered signaling pathways, and potential cell-cell crosstalk in the development of AKI. These data reveal new insights into the pathogenesis and potential therapeutic strategies in ischemic AKI.

Dataset Information

Single-cell analysis reveals immune landscape in kidneys of patients with chronic transplant rejection.

Publications

Single-cell analysis reveals immune landscape in kidneys of patients with chronic transplant rejection.

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