Nephron progenitor cells (NPCs) self-renew and differentiate into nephrons, the functional units 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 (hPSCs). Molecular analyses demonstrated that cultured iNPCs closely resemble 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, the 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 genes associated with kidney development and disease. 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.

肾单位祖细胞 (NPC) 自我更新并分化为肾单位，即肾脏的功能单位。在这里，p38 和 YAP 活性的操纵允许原代小鼠和人类 NPC 的长期克隆扩增，以及来自人类多能干细胞 (hPSC) 的诱导 NPC (iNPC)。分子分析表明，培养的 iNPC 与原代人类 NPC 非常相似。相对于已发表的人肾类器官方案，iNPC 生成的肾单位类器官具有最少的脱靶细胞类型，并且足细胞的成熟度增强。令人惊讶的是，NPC 培养基发现了人类足细胞程序的可塑性，使足细胞能够重编程为类似 NPC 的状态。基因组编辑的可扩展性和简便性促进了 NPC 培养中的全基因组 CRISPR 筛选，揭示了与肾脏发育和疾病相关的基因。此外，NPC 指导的常染色体显性多囊肾病 (ADPKD) 模型确定了一种囊肿发生的小分子抑制剂。这些发现凸显了所报道的 iNPC 平台在肾脏发育、疾病、可塑性和再生研究中的广泛应用。