Axial nephron fate switching demonstrates a plastic system tunable on demand.
Publication Year:
2025
PubMed ID:
40855070
Funding Grants:
Public Summary:
The human kidney contains about a million nephrons—tiny tubular structures that filter blood and maintain fluid balance—but how these nephrons develop specialized cells is not fully understood. In this study, researchers used stem-cell–derived kidney organoids, which produce hundreds of synchronized nephrons, to study how nephron cells acquire their identities. By analyzing these organoids alongside developing human kidneys, they discovered that nephron cell types are controlled by three key signaling pathways: WNT, BMP, and FGF. Manipulating these pathways allowed them to shift cells between different nephron regions, demonstrating that nephron development is highly flexible. This work helps explain how kidney cells form during development and provides a foundation for generating specific nephron cells for research or therapeutic purposes.
Scientific Abstract:
The human nephron is a highly patterned tubular structure that develops specialized cells to regulate bodily fluid homeostasis, blood pressure, and urine secretion throughout life. Approximately 1 million nephrons form in each kidney during embryonic and fetal development, but how they develop is poorly understood. Here, we interrogate axial patterning mechanisms in the human nephron using an iPSC-derived kidney organoid system that generates hundreds of developmentally synchronized nephrons, and we compare it to in vivo human kidney development using single cell and spatial transcriptomic approaches. We show that human nephron patterning is controlled by integrated WNT/BMP/FGF signaling. Imposing a WNT(ON)/BMP(OFF) state established a distal nephron identity that matures into thick ascending loop of Henle cells by endogenously activating FGF. Simultaneous suppression of FGF signaling switches cells back to a proximal cell-state, a transformation that is in itself dependent on BMP signal transduction. Our system highlights plasticity in axial nephron patterning, delineates the roles of WNT, FGF, and BMP mediated mechanisms controlling nephron patterning, and paves the way for generating nephron cells on demand.
