Human pluripotent stem cell-derived kidney organoids reveal tubular epithelial pathobiology of heterozygousHNF1B-associated dysplastic kidney malformations

Ioannis Bantounas; Kirsty M. Rooney; Filipa M. Lopes; Faris Tengku; Steven Woods; Leo A. H. Zeef; Shweta Y. Kuba; Nicola Bates; Sandra Hummelgaard; Katherine A Hillman; Silvia Cereghini; Adrian S. Woolf; Susan J. Kimber

doi:10.1101/2023.03.14.532598

Human pluripotent stem cell-derived kidney organoids reveal tubular epithelial pathobiology of heterozygousHNF1B-associated dysplastic kidney malformations

Ioannis Bantounas, Kirsty M. Rooney, Filipa M. Lopes, Faris Tengku, Steven Woods, Leo A. H. Zeef, Shweta Y. Kuba, Nicola Bates, Sandra Hummelgaard, Katherine A Hillman, Silvia Cereghini, Adrian S. Woolf, Susan J. Kimber

SHLS Life Sciences

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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. Numerous genes implicated in Mendelian kidney tubulopathies were downregulated, and mutant tubules resisted the cAMP-mediated dilatation seen in controls. Bioinformatic analyses indicated abnormal WNT, calcium, and glutamatergic pathways, the latter hitherto unstudied in developing kidneys. Glutamate ionotropic receptor kainate type subunit 3 was upregulated in mutant organoids and was detected in their tubules and in fetal human DKM dysplastic epithelia. These results reveal morphological, molecular, and physiological roles for HNF1B in human kidney tubule morphogenesis and functional differentiation. They additionally suggest druggable targets to ameliorate disease.

Original language	English
Journal	bioRxiv
DOIs	https://doi.org/10.1101/2023.03.14.532598
Publication status	Submitted - 15 Mar 2023

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Bantounas, I., Rooney, K. M., Lopes, F. M., Tengku, F., Woods, S., Zeef, L. A. H., Kuba, S. Y., Bates, N., Hummelgaard, S., Hillman, K. A., Cereghini, S., Woolf, A. S., & Kimber, S. J. (2023). Human pluripotent stem cell-derived kidney organoids reveal tubular epithelial pathobiology of heterozygousHNF1B-associated dysplastic kidney malformations. Manuscript submitted for publication. https://doi.org/10.1101/2023.03.14.532598

@article{64f2ef146c964c119713c79c9bf9d61f,

title = "Human pluripotent stem cell-derived kidney organoids reveal tubular epithelial pathobiology of heterozygousHNF1B-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. Numerous genes implicated in Mendelian kidney tubulopathies were downregulated, and mutant tubules resisted the cAMP-mediated dilatation seen in controls. Bioinformatic analyses indicated abnormal WNT, calcium, and glutamatergic pathways, the latter hitherto unstudied in developing kidneys. Glutamate ionotropic receptor kainate type subunit 3 was upregulated in mutant organoids and was detected in their tubules and in fetal human DKM dysplastic epithelia. These results reveal morphological, molecular, and physiological roles for HNF1B in human kidney tubule morphogenesis and functional differentiation. They additionally suggest druggable targets to ameliorate disease.",

author = "Ioannis Bantounas and Rooney, {Kirsty M.} and Lopes, {Filipa M.} and Faris Tengku and Steven Woods and Zeef, {Leo A. H.} and Kuba, {Shweta Y.} and Nicola Bates and Sandra Hummelgaard and Hillman, {Katherine A} and Silvia Cereghini and Woolf, {Adrian S.} and Kimber, {Susan J.}",

year = "2023",

month = mar,

day = "15",

doi = "10.1101/2023.03.14.532598",

language = "English",

journal = "bioRxiv",

}

Bantounas, I, Rooney, KM, Lopes, FM, Tengku, F, Woods, S, Zeef, LAH, Kuba, SY, Bates, N, Hummelgaard, S, Hillman, KA, Cereghini, S, Woolf, AS & Kimber, SJ 2023, 'Human pluripotent stem cell-derived kidney organoids reveal tubular epithelial pathobiology of heterozygousHNF1B-associated dysplastic kidney malformations', bioRxiv. https://doi.org/10.1101/2023.03.14.532598

TY - JOUR

T1 - Human pluripotent stem cell-derived kidney organoids reveal tubular epithelial pathobiology of heterozygousHNF1B-associated dysplastic kidney malformations

AU - Bantounas, Ioannis

AU - Rooney, Kirsty M.

AU - Lopes, Filipa M.

AU - Tengku, Faris

AU - Woods, Steven

AU - Zeef, Leo A. H.

AU - Kuba, Shweta Y.

AU - Bates, Nicola

AU - Hummelgaard, Sandra

AU - Hillman, Katherine A

AU - Cereghini, Silvia

AU - Woolf, Adrian S.

AU - Kimber, Susan J.

PY - 2023/3/15

Y1 - 2023/3/15

N2 - 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. Numerous genes implicated in Mendelian kidney tubulopathies were downregulated, and mutant tubules resisted the cAMP-mediated dilatation seen in controls. Bioinformatic analyses indicated abnormal WNT, calcium, and glutamatergic pathways, the latter hitherto unstudied in developing kidneys. Glutamate ionotropic receptor kainate type subunit 3 was upregulated in mutant organoids and was detected in their tubules and in fetal human DKM dysplastic epithelia. These results reveal morphological, molecular, and physiological roles for HNF1B in human kidney tubule morphogenesis and functional differentiation. They additionally suggest druggable targets to ameliorate disease.

AB - 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. Numerous genes implicated in Mendelian kidney tubulopathies were downregulated, and mutant tubules resisted the cAMP-mediated dilatation seen in controls. Bioinformatic analyses indicated abnormal WNT, calcium, and glutamatergic pathways, the latter hitherto unstudied in developing kidneys. Glutamate ionotropic receptor kainate type subunit 3 was upregulated in mutant organoids and was detected in their tubules and in fetal human DKM dysplastic epithelia. These results reveal morphological, molecular, and physiological roles for HNF1B in human kidney tubule morphogenesis and functional differentiation. They additionally suggest druggable targets to ameliorate disease.

U2 - 10.1101/2023.03.14.532598

DO - 10.1101/2023.03.14.532598

M3 - Article

JO - bioRxiv

JF - bioRxiv

ER -

Human pluripotent stem cell-derived kidney organoids reveal tubular epithelial pathobiology of heterozygousHNF1B-associated dysplastic kidney malformations

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