可长期扩增的小鼠和人类诱导肾小球祖细胞实现了肾脏类器官的成熟以及可塑性和疾病模型的建立

IF 19.8 1区 医学 Q1 CELL & TISSUE ENGINEERING
Biao Huang, Zipeng Zeng, Sunghyun Kim, Connor C. Fausto, Kari Koppitch, Hui Li, Zexu Li, Xi Chen, Jinjin Guo, Chennan C. Zhang, Tianyi Ma, Pedro Medina, Megan E. Schreiber, Mateo W. Xia, Ariel C. Vonk, Tianyuan Xiang, Tadrushi Patel, Yidan Li, Riana K. Parvez, Balint Der, Zhongwei Li
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引用次数: 0

摘要

肾小球祖细胞(NPC)可自我更新并分化成肾小球,肾小球是肾脏的功能单位。在这里,通过操纵 p38 和 YAP 活性,小鼠和人类原代肾小球原代细胞以及来自人类多能干细胞(hPSCs)的诱导肾小球原代细胞(iNPCs)得以长期克隆扩增。分子分析表明,培养出的 iNPCs 与原代人类 NPCs 非常相似。iNPCs 生成的肾脏器官组织与已公布的人类肾脏器官组织方案相比,具有最小的脱靶细胞类型和更高的荚膜细胞成熟度。令人惊讶的是,NPC 培养基揭示了人类荚膜细胞程序的可塑性,使荚膜细胞重编程为类似 NPC 的状态。基因组编辑的可扩展性和简易性促进了NPC培养中的全基因组CRISPR筛选,发现了与肾脏发育和疾病相关的基因。此外,NPC 引导的常染色体显性多囊肾病(ADPKD)建模还发现了一种小分子囊肿生成抑制剂。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。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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

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

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.

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来源期刊
Cell stem cell
Cell stem cell 生物-细胞生物学
CiteScore
37.10
自引率
2.50%
发文量
151
审稿时长
42 days
期刊介绍: Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.
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