Cell-Cell Communication in Embryonic Kidney Development: Insights from Single-Cell and Spatial Transcriptomics

Embryonic kidney morphogenesis depends on the coordinated communication among ureteric epithelium, nephron progenitors, stroma, endothelium and differentiating nephrons. Classical studies established central roles for glial cell line-derived neurotrophic factor (GDNF) signaling through the RET proto-oncogene receptor tyrosine kinase (RET), WNT-family signaling, fibroblast growth factor (FGF), bone morphogenetic protein (BMP), Notch, Hedgehog, vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) pathways, but pathway-centered models do not fully explain why similar signals produce different outcomes across cell states, anatomical locations and developmental stages. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics have refined these models by resolving heterogeneous progenitor, stromal and vascular states, reassigning several signal sources and constraining predicted interactions to defined tissue relationships. Here, we examine how these findings change the interpretation of ureteric bud (UB) branching, nephron progenitor transitions, stromal patterning and vascular integration. We use the dynamic developmental niche as an evidence-organizing framework, rather than as a new biological entity, to distinguish established mechanisms from relationships supported mainly by transcriptomic, spatial or computational evidence. Vascular, immune and mechanical interactions are evaluated according to their model-specific support, and we outline experiments required to connect predicted communication with morphogenetic outcomes and congenital anomalies of the kidney and urinary tract (CAKUT).