Nephron progenitors rhythmically alternate between renewal and differentiation phases that synchronize with kidney branching morphogenesis

Abstract

The mammalian kidney achieves massive parallelization of function by exponentially duplicating nephron-forming niches during development. Each niche caps a tip of the ureteric bud epithelium (the future urinary collecting duct tree) as it undergoes branching morphogenesis, while nephron progenitors within niches balance self-renewal and differentiation to early nephron cells. Nephron formation rate approximately matches branching rate over a large fraction of mouse gestation, yet the nature of this apparent pace-maker is unknown. Here we correlate spatial transcriptomics data with branching ‘life-cycle’ to discover rhythmically alternating signatures of nephron progenitor differentiation and renewal across Wnt, retinoic acid (RA), Hippo-Yap and other pathways. We then reveal stark differences in progenitor renewal vs. differentiation rates depending on whether Yap is activated in- or out-of-phase with Wnt/β-catenin-induced differentiation of human stem-cell derived nephron progenitor organoids. Our data brings temporal resolution to the renewal vs. differentiation balance in the nephrogenic niche, and informs new strategies to achieve self-sustaining niches in synthetic human kidney tissues.