Identification of a core transcriptional program driving the human renal mesenchymal-to-epithelial transition

During kidney development, nephron epithelia arise de novo from fate-committed mesenchymal progenitors through a mesenchymal-to-epithelial transition (MET). Downstream of fate specification, transcriptional mechanisms that drive establishment of epithelial morphology through MET are poorly understood. We used human renal organoids derived from induced pluripotent stem cells, which recapitulate nephrogenesis, to investigate mechanisms controlling the renal MET programme. Multi-ome profiling of organoids revealed dynamic changes in gene expression and chromatin accessibility driven by transcriptional activators and repressors throughout renal MET. CRISPR-interference-based gene perturbation revealed that PAX8 is essential for initiation of MET in human renal organoids, contrary to mouse, by activating a cell adhesion programme. Furthermore, while Wnt/β-Catenin signalling specifies nephron fate, we find that it must be attenuated to allow HNF1B and TEAD transcription factors to drive completion of MET. These results reveal how the developing kidney balances fate-commitment and morphogenesis with implications for understanding both developmental kidney diseases and aberrant epithelial plasticity following adult renal tubular injury.