Abstract
BackgroundAutophagy is believed to participate in embryonic development, but whether the expression of autophagy-associated genes undergoes changes during the development of human embryonic kidneys remains unknown.MethodsIn this work, we identified 36,151 human renal cells from embryonic kidneys of 9–18 gestational weeks in 16 major clusters by single-cell RNA sequencing (scRNA-seq), and detected 1350 autophagy-related genes in all fetal renal cells. The abundance of each cell cluster in Wilms tumor samples from scRNA-seq and GDC TARGET WT datasets was detected by CIBERSORTx. R package Monocle 3 was used to determine differentiation trajectories. Cyclone tool of R package scran was applied to calculate the cell cycle scores. R package SCENIC was used to investigate the transcriptional regulons. The FindMarkers tool from Seurat was used to calculate DEGs. GSVA was used to perform gene set enrichment analyses. CellphoneDB was utilized to analyze intercellular communication.ResultsIt was found that cells in the 13th gestational week showed the lowest transcriptional level in each cluster in all stages. Nephron progenitors could be divided into four subgroups with diverse levels of autophagy corresponding to different SIX2 expressions. SSBpod (podocyte precursors) could differentiate into four types of podocytes (Pod), and autophagy-related regulation was involved in this process. Pseudotime analysis showed that interstitial progenitor cells (IPCs) potentially possessed two primitive directions of differentiation to interstitial cells with different expressions of autophagy. It was found that NPCs, pretubular aggregates and interstitial cell clusters had high abundance in Wilms tumor as compared with para-tumor samples with active intercellular communication.ConclusionsAll these findings suggest that autophagy may be involved in the development and cellular heterogeneity of early human fetal kidneys. In addition, part of Wilms tumor cancer cells possess the characteristics of some fetal renal cell clusters.Graphical abstract
Highlights
The development of human kidneys starts in the intermediate mesoderm via communication between the ureteric bud (UB) and metanephric mesenchyme (MM), which are surrounded by mesenchymal cellWen‐jin et al Cancer Cell Int (2021) 21:460 clusters termed cap mesenchyme (CM) [1]
In addition to endothelial cells and leukocytes, we identified 10 cap mesenchyme derived cells, including Nephron progenitor cells (NPC), pretubular aggregate (PTA), renal vesicle and comma-shaped body (RVCSB), S-shaped body (SSB) medial and distal cells (SSBmd), SSB proximal cells (SSBpr), SSB podocytes (SSBpod), podocytes (Pods), early proximal tubule (ErPrT), distal tubule and loop of Henle (DTLH), and connecting tubule (CnT); and three stromal derived cells, including interstitial progenitor cells (IPC), Interstitial cells (IC) and mesangial cells (Mes), which were presented in the UMAP plot (Fig. 1a)
An overview of the cell cycle score heatmap showed no significant difference between different cell types, indicating that no cluster was affected by cell cycle
Summary
The development of human kidneys starts in the intermediate mesoderm via communication between the ureteric bud (UB) and metanephric mesenchyme (MM), which are surrounded by mesenchymal cellWen‐jin et al Cancer Cell Int (2021) 21:460 clusters termed cap mesenchyme (CM) [1]. Nephron progenitor cells (NPCs) originate from CM and transform into various nephrons through strict regulation of gene expression [3]. There exist species diversities in renal development or mature kidneys between rodents and humans [11]. Several recent studies using single-cell RNA sequencing (scRNA-seq) to explore gene profiles have reported the molecular markers and dynamic gene expression in both rodents and humans [2, 5, 12,13,14], the cellular heterogeneity and corresponding gene pathways of initiating cells such as NPCs that are associated with the development of some renal diseases remain unclear. Autophagy is believed to participate in embryonic development, but whether the expression of autophagy-associated genes undergoes changes during the development of human embryonic kidneys remains unknown
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