肝细胞核因子 1B (HNF1B) 编码在发育中的人肾上皮细胞中表达的转录因子。杂合 HNF1B 突变是发育不良性肾畸形 (DKM) 的最常见单基因原因。为了了解其病理生物学，我们从 CRISPR-Cas9 基因编辑的人胚胎干细胞 (ESC) 和从具有 HNF1B 相关 DKM 的家族中重新编程的诱导多能干细胞 (iPSC) 中生成了杂合 HNF1B 突变肾类器官。突变类器官含有增大的畸形小管，显示出细胞周转失调。许多与孟德尔肾小管病有关的基因被下调，突变的肾小管抵抗了对照中观察到的环磷酸腺苷 (cAMP) 介导的扩张。大量和单细胞 RNA 测序 (scRNA-seq) 分析表明 Wingless/Integrated (WNT)、钙和谷氨酸途径异常，后者在发育中的肾脏中迄今尚未进行研究。谷氨酸离子型受体红藻氨酸盐型亚基 3 (GRIK3) 在畸形突变肾单位中表达上调，并在 HNF1B 突变胎儿人发育不良肾上皮细胞中显着表达。这些结果揭示了 HNF1B 在人肾小管分化和形态发生中的形态、分子和生理作用，阐明了突变型 HNF1B 引起的肾脏疾病的发育起源。版权所有 © 2024。由 Elsevier Inc. 出版。

Hepatocyte nuclear factor 1B (HNF1B) encodes a transcription factor expressed in developing human kidney epithelia. Heterozygous HNF1B mutations are the commonest monogenic cause of dysplastic kidney malformations (DKMs). To understand their pathobiology, we generated heterozygous HNF1B mutant kidney organoids from CRISPR-Cas9 gene-edited human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) reprogrammed from a family with HNF1B-associated DKMs. Mutant organoids contained enlarged malformed tubules displaying deregulated cell turnover. Numerous genes implicated in Mendelian kidney tubulopathies were downregulated, and mutant tubules resisted the cyclic AMP (cAMP)-mediated dilatation seen in controls. Bulk and single-cell RNA sequencing (scRNA-seq) analyses indicated abnormal Wingless/Integrated (WNT), calcium, and glutamatergic pathways, the latter hitherto unstudied in developing kidneys. Glutamate ionotropic receptor kainate type subunit 3 (GRIK3) was upregulated in malformed mutant nephron tubules and prominent in HNF1B mutant fetal human dysplastic kidney epithelia. These results reveal morphological, molecular, and physiological roles for HNF1B in human kidney tubule differentiation and morphogenesis illuminating the developmental origin of mutant-HNF1B-causing kidney disease.Copyright © 2024. Published by Elsevier Inc.