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Abstract
ABSTRACTThe 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.
Highlights
The development of the embryonic kidney is a paradigm for the complex inductive and regulatory mechanisms driving organogenesis (Grobstein, 1953)
A violin plot showing the expression of a representative gene and a heat map with the expression of the five most significantly differentially expressed genes for each cluster are shown in Fig. 1B and C, respectively. This analysis identifies most of the cell types expected in a developing kidney, from undifferentiated cap mesenchyme to differentiated epithelia, stroma, endothelial and immune cells as well as erythrocytes
The analysis of single-cell RNA sequencing of human embryonic kidneys provides a powerful tool with which to dissect the gene expression profile during renal organogenesis
Summary
The development of the embryonic kidney is a paradigm for the complex inductive and regulatory mechanisms driving organogenesis (Grobstein, 1953). The UB tip cells release signals to the mesenchyme to maintain its self-renewal These signaling cascades are crucial for UB outgrowth and branching, and involve a host of morphogens and signaling networks, including Gdnf-Ret, Wnt, Fgf and Notch signaling, to name a few (Cacalano et al, 1998; Lu et al, 2009; Pachnis et al, 1993; Pichel et al, 1996; Schuchardt et al, 1994). These signaling events regulate the balance between self-renewal and differentiation of nephron progenitors (Carroll et al, 2005; Park et al, 2007), ensure proper positioning of the metanephric mesenchyme (MM) and UB outgrowth (Huang et al, 2014; Pietilä et al, 2016; Yun and Perantoni, 2017), and promote further differentiation into specific cell types (Cheng et al, 2007; Surendran et al, 2010)
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