Single-cell analysis of progenitor cell dynamics and lineage specification in the human fetal kidney

Abstract

The mammalian kidney develops through reciprocal interactions between the ureteric bud and the metanephric mesenchyme to give rise to the entire collecting system and the nephrons. Most of our knowledge of the developmental regulators driving this process arises from the study of gene expression and functional genetics in mice and other animal models. In order to shed light on human kidney development, we have used single-cell transcriptomics to characterize gene expression in different cell populations, and to study individual cell dynamics and lineage trajectories during development. Single-cell transcriptome analyses of 6414 cells from five individual specimens identified 11 initial clusters of specific renal cell types as defined by their gene expression profile. Further subclustering identifies progenitors, and mature and intermediate stages of differentiation for several renal lineages. Other lineages identified include mesangium, stroma, endothelial and immune cells. Novel markers for these cell types were revealed in the analysis, as were components of key signaling pathways driving renal development in animal models. Altogether, we provide a comprehensive and dynamic gene expression profile of the developing human kidney at the single-cell level.

A new Elf5CreERT2‐GFP BAC transgenic mouse model for tracing Elf5 cell lineages in adult tissues

“…This confirms that Elf5 expression is restricted to the water channel expressing principal cell types within the collecting ducts of adult mouse kidney. The restriction of Elf5 expression in the kidney to the collecting ducts is conserved in human kidneys as recently determined by single cell RNA sequencing studies .…”

Cellular and molecular determinants of normal and abnormal kidney development

“…The second is the development of technologies to sequence the transcriptome of individual cells which are providing considerable insights into the developmental trajectory of fetal progenitors, particularly those involved in directing the differentiation of nephron progenitor cells. Analysis of cells from both human and mouse kidneys have provided key insights into the timed recruitment of progenitor cells into the nephron forming niche (Lindstrom, De Sena Brandine, et al, ), elucidated the cellular origin of renal tumors (Young et al, ), helped to define the lineage restrictions involved in organ development (Menon et al, ) and identified genes important for regulating the metabolic repertoire of developing nephron segments (P. Wang et al, ). Examining these developmental trajectories and cellular phenotypes in organs from CAKUT patients and/or mouse models will be central to providing a new appreciation of how disease develops in the fetal kidney.…”

Kidney organoids: accurate models or fortunate accidents

“…This convergence has accelerated the characterization of cell types, marker genes, and inferred lineage relationships in human kidney development. Covering an age range of 7-25 wk of embryonic development, several studies resolved clusters representing cell types from the stromal, nephron, and ureteric epithelium lineages as well as endothelial, blood, and immune cells ( Table 1; Lindstrom et al 2018a,b;Menon et al 2018;Wang et al 2018;Young et al 2018;Hochane et al 2019). One study also detected a low number of neural precursor cells (Young et al 2018).…”

“…Pseudotime analysis of single cells is a computational method to organize the transcriptional profiles of each cell along a developmental trajectory, enabling inference of cell state transitions and lineage relationships (Trapnell et al 2014). Such analyses applied to single cells from the human fetal kidney largely replicate the expected developmental trajectory from nephron progenitor to more mature nephron cell states though the branch points identifying the divergence between progenitor and podocyte, proximal, and distal nephron fates vary between studies (Lindstrom et al 2018a;Menon et al 2018;Wang et al 2018;Hochane et al 2019). For example, Lindstrom et al (2018a) report human podocytes developing along a trajectory distinct from the precursors of the proximal and distal nephron, whereas results from Hochane et al (2019) identify podocytes diverging after a common precursor state that also gives rise to proximal and distal tubular fates.…”