Progressive Recruitment of Mesenchymal Progenitors Reveals a Time-Dependent Process of Cell Fate Acquisition in Mouse and Human Nephrogenesis

Mammalian nephrons arise from a limited nephron progenitor pool through a reiterative inductive process extending over days (mouse) or weeks (human) of kidney development. Here, we present evidence that human nephron patterning reflects a time-dependent process of recruitment of mesenchymal progenitors into an epithelial nephron precursor. Progressive recruitment predicted from high-resolution image analysis and three-dimensional reconstruction of human nephrogenesis was confirmed through direct visualization and cell fate analysis of mouse kidney organ cultures. Single-cell RNA sequencing of the human nephrogenic niche provided molecular insights into these early patterning processes and predicted developmental trajectories adopted by nephron progenitor cells in forming segment-specific domains of the human nephron. The temporal-recruitment model for nephron polarity and patterning suggested by direct analysis of human kidney development provides a framework for integrating signaling pathways driving mammalian nephrogenesis. [Display omitted] •Imaging shows gradual recruitment of progenitors into forming human/mouse nephrons•Single-cell RNA sequencing tracks cellular heterogeneity in human nephrogenesis•Divergent molecular trajectories generate distinct regions of the human nephron During kidney development, mammalian nephrons arise from a limited progenitor pool through a reiterative inductive process. Lindström et al. demonstrate that human and mouse nephron patterning involves gradual mesenchymal progenitor cell recruitment into the epithelial nephron precursor. Recruitment timing predicts precursor cell position and eventual fate in functional nephron structures.