A high-definition spatiotemporal transcriptomic atlas of mammalian kidney development.

The structural composition of organs undergoes significant transformations during organogenesis, laying the foundation for their eventual functional architecture. In contrast, adult organs maintain structural homeostasis. However, the dynamics of organ structure during the organogenesis and homeostasis stages remain poorly understood. Here, we present a spatially resolved transcriptome atlas at single-cell resolution to explore the establishment and maintenance of kidney structure in mice. Our analysis reveals 40 migration-related cell-cell communication events during kidney organogenesis. Contrary to the traditional two-layer model (cortex and medulla), we demonstrate that the kidney develops a five-layer structure over time. Mechanistically, migration-related cell-cell communication drives this structural formation, with ephrin-A5 (Efna5) playing a key role in forming three distinct layers within the medulla. The spatial distribution of specific cell types and their gene expression patterns within these five layers likely enhances renal adaptation to hypoxic and hyperosmotic environments. Furthermore, Frizzled 4 receptor (Fzd4) is critical for the morphogenesis of the U-shaped loop of Henle (LoH). In the adult stage, when structural homeostasis prevails, only three migration-related ligand-receptor pairs are observed, and a stable four-layer structure is maintained due to the absence of progenitor cells. Overall, our findings illustrate the role of intercellular communication in driving the transition from structural establishment during organogenesis to stable maintenance in homeostasis. These insights provide new avenues for advancing organ regeneration strategies.