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Stem Cell Reports ; 19(6): 859-876, 2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38788724

RESUMEN

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.


Asunto(s)
Factor Nuclear 1-beta del Hepatocito , Células Madre Pluripotentes Inducidas , Organoides , Humanos , Factor Nuclear 1-beta del Hepatocito/genética , Factor Nuclear 1-beta del Hepatocito/metabolismo , Organoides/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Diferenciación Celular/genética , Heterocigoto , Túbulos Renales/patología , Túbulos Renales/metabolismo , Mutación , Riñón/patología , Riñón/metabolismo , Riñón/anomalías , Sistemas CRISPR-Cas , Células Madre Pluripotentes/metabolismo , Edición Génica
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