Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Human pluripotent stem cell-derived kidney organoids reveal tubular epithelial pathobiology of heterozygous HNF1B-associated dysplastic kidney malformations

ABSTRACT: 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 ESCs and iPSCs reprogrammed from a family with HNF1B-asscociated DKMs. Mutant organoids contained enlarged malformed tubules and displayed deregulated cell turnover. This submission contains kidney tissue samples.

INSTRUMENT(S): Illumina HiSeq 4000

ORGANISM(S): Homo sapiens

SUBMITTER: Leo Zeef

PROVIDER: E-MTAB-12822 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Heterozygous mutations in HNF1B cause the complex syndrome Renal Cysts and Diabetes (RCAD), characterized by developmental abnormalities of kidney, genital tracts and pancreas and a variety of renal, pancreas and liver dysfunctions. The pathogenesis underlying this syndrome remained unclear since mice with Hnf1b heterozygous null mutations have no phenotype, while constitutive/conditional Hnf1b-ablation led to more severe phenotypes. We generated a novel mouse model carrying an identified human mutation at the intron-2 splice donor-site. Reflecting the disease and unlike previous heterozygous, heterozygous for the splicing mutation exhibited decreased HNF1B protein levels and bilateral renal cysts from embryonic stage E15, originated from glomeruli, early proximal tubules (PT) and intermediate nephron segments, concurrently with a delayed PT differentiation, hydronephrosis and rare genital tract anomalies. To further elucidate the cellular and molecular components sensitive to HNF1B levels, we performed RNA-sequencing on WT and heterozygous mutant kidneys at E14.5 (considered morphologically as pre-disease kidneys) and at disease stages (E15.5, E17.5 and P1). Consistent with the histological and immunhistochemical findings, these analysis showed that most down-regulated genes in embryonic kidneys were primarily expressed in early PTs and Henle’s Loop and involved in ion/drug transport, organic acid and lipid metabolic processes, while previous targets identified upon Hnf1b-ablation, including the cystic disease genes, were weakly or no affected. Postnatal analyses revealed renal abnormalities, ranging from glomerular cysts to hydronephrosis and rarely multicystic dysplasia. Urinary proteomics uncovered a particular profile predictive of progressive decline in kidney function, injury and fibrosis, and displayed common features with a recently reported urine proteome in a RCAD pediatric cohort. Our results show that HNF1B reduced levels lead to developmental disease phenotypes associated with the deregulation of a subset of its targets and further suggests that this new model represents a unique clinical/pathological viable model of the RCAD disease.

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Human pluripotent stem cell-derived kidney organoids reveal tubular epithelial pathobiology of heterozygous HNF1B-associated dysplastic kidney malformations

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