Long-term expandable mouse and human-induced nephron progenitor cells enable kidney organoid maturation and modeling of plasticity and disease

• Published in: Cell stem cell Vol. 31; no. 6; pp. 921 - 939.e17
• Main Authors: Huang, Biao, Zeng, Zipeng, Kim, Sunghyun, Fausto, Connor C., Koppitch, Kari, Li, Hui, Li, Zexu, Chen, Xi, Guo, Jinjin, Zhang, Chennan C., Ma, Tianyi, Medina, Pedro, Schreiber, Megan E., Xia, Mateo W., Vonk, Ariel C., Xiang, Tianyuan, Patel, Tadrushi, Li, Yidan, Parvez, Riana K., Der, Balint, Chen, Jyun Hao, Liu, Zhenqing, Thornton, Matthew E., Grubbs, Brendan H., Diao, Yarui, Dou, Yali, Gnedeva, Ksenia, Ying, Qilong, Pastor-Soler, Nuria M., Fei, Teng, Hallows, Kenneth R., Lindström, Nils O., McMahon, Andrew P., Li, Zhongwei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.06.2024
• Subjects: Animals; CAKUT; Cell Differentiation; cellular plasticity; congenital anomalies of the kidney and urinary tract; CRISPR screen; Gene Editing; hPSC; human pluripotent stem cell; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Kidney - pathology; kidney organoid; Mice; Models, Biological; nephron progenitor cell; Nephrons - cytology; NPC; Organoids - cytology; Organoids - metabolism; PKD; podocyte; Podocytes - cytology; Podocytes - metabolism; polycystic kidney disease; Polycystic Kidney, Autosomal Dominant - genetics; Polycystic Kidney, Autosomal Dominant - metabolism; Polycystic Kidney, Autosomal Dominant - pathology; Wilms tumor; NPC; nephron progenitor cell; CAKUT; congenital anomalies of the kidney and urinary tract; hPSC; PKD; polycystic kidney disease; human pluripotent stem cell; podocyte; Wilms tumor; cellular plasticity; CRISPR screen; kidney organoid
• ISSN: 1934-5909; 1875-9777; 1875-9777
• DOI: 10.1016/j.stem.2024.04.002

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. [Display omitted] •YAP activation allows long-term expansion of hPSC-iNPCs•iNPC-derived nephron organoids generate mature podocytes with limited off-target cells•Podocyte-to-NPC reprogramming with hNPSR-v2 medium reveals human podocyte plasticity•Genome-wide CRISPR screening and PKD modeling from genome-edited NPC lines Nephron progenitor cells (NPCs) generate nephrons, the functional units of the kidney. Li and colleagues develop systems for long-term expansion of mouse and human NPCs, which can further develop into mature nephron organoids. These in vitro systems generate novel insights into kidney development and disease and reveal human nephron plasticity.