Long term expandable mouse and human induced nephron progenitor cells enable organoid modeling of kidney maturation, plasticity and disease
Description
Nephron progenitor cells (NPCs) self-renew and differentiate into nephrons, the functional unit of the kidney. Here, manipulation of p38 and YAP activity allowed for long-term clonal expansion of primary mouse and human NPCs, and induced NPCs (iNPCs) from human pluripotent stem cells. Molecular analyses demonstrated cultured iNPCs resemble closely primary human NPCs. iNPCs generated nephron organoids with minimal off-target cell types and enhanced maturation of podocytes relative to published human kidney organoid protocols. Surprisingly, NPC culture medium uncovered plasticity in human podocyte programs, enabling podocyte reprogramming to an NPC-like state. Scalability and ease of genome-editing facilitated genome-wide CRISPR screening in NPC culture, uncovering novel genes associated with kidney development and dis-ease. Further, NPC-directed modeling of autosomal-dominant polycystic kidney disease (ADPKD) identified a small molecule inhibitor of cystogenesis. These findings highlight a broad application for the reported iNPC platform in the study of kidney development, disease, plasticity, and regeneration.