An HNF1α truncation associated with maturity-onset diabetes of the young impairs pancreatic progenitor differentiation by antagonizing HNF1β function

Cujba, Ana-Maria; Fallas, Mario Enrique Alvarez; Pedraza‐Arevalo, Sergio; Laddach, Anna; Shepherd, Maggie; Hattersley, Andrew T.; Watt, Fiona M.; Sancho, Rocı́o

doi:10.1016/j.celrep.2022.110425

Cited by 23 publications

(23 citation statements)

References 75 publications

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“…Mutations in HNF1A introduced by Cardenas-Diaz are located adjacent to the start codon, excluding possible dominant-negative effects of a truncated protein. Such dominant-negative truncating mutations were made by another group and shown to affect pancreatic differentiation from pluripotent stem cells by interfering with HNF1B function 46 . Both our study and Cardenas-Diaz et al identify a deficiency of glucose-stimulated insulin secretion in HNF1A biallelic knockout cells 45 .…”

Section: Discussionmentioning

confidence: 99%

Reduced calcium levels and accumulation of abnormal insulin granules in stem cell models of HNF1A deficiency

et al. 2022

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Mutations in HNF1A cause Maturity Onset Diabetes of the Young (HNF1A-MODY). To understand mechanisms of β-cell dysfunction, we generated stem cell-derived pancreatic endocrine cells with hypomorphic mutations in HNF1A. HNF1A-deficient β-cells display impaired basal and glucose stimulated-insulin secretion, reduced intracellular calcium levels in association with a reduction in CACNA1A expression, and accumulation of abnormal insulin granules in association with SYT13 down-regulation. Knockout of CACNA1A and SYT13 reproduce the relevant phenotypes. In HNF1A deficient β-cells, glibenclamide, a sulfonylurea drug used in the treatment of HNF1A-MODY patients, increases intracellular calcium, and restores insulin secretion. While insulin secretion defects are constitutive in β-cells null for HNF1A, β-cells heterozygous for hypomorphic HNF1A (R200Q) mutations lose the ability to secrete insulin gradually; this phenotype is prevented by correction of the mutation. Our studies illuminate the molecular basis for the efficacy of treatment of HNF1A-MODY with sulfonylureas, and suggest promise for the use of cell therapies.

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Section: Discussionmentioning

confidence: 99%

Reduced calcium levels and accumulation of abnormal insulin granules in stem cell models of HNF1A deficiency

et al. 2022

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“… 397 CRISPR-Cas9-engineered human iPSCs with truncated HNF1α p291FsinSCs grown as 3D pancreatic organoids were shown to abolish HNF1β function and reduce pancreatic progenitor and β-cell differentiation. 398 Angiotensin converting enzyme 2 (ACE2)-specific knockout gut organoids show decreased Lgr5 and Ki67 levels. 399 Endoplasmic reticulum membrane protein complex subunit 3 (Emc3) is a determinant of the maintenance of gut mucous homeostasis, and the knockout of Emc3 led to enhanced endoplasmic reticulum (ER) pressure and destroyed Paneth cell function in the stem cell niche, leading to the failure of the culture of gut organoids.…”

Section: Digestive System Organoid Models and Precision And Personali...mentioning

confidence: 99%

Applications of human organoids in the personalized treatment for digestive diseases

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Jin

et al. 2022

Sig Transduct Target Ther

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Digestive system diseases arise primarily through the interplay of genetic and environmental influences; there is an urgent need in elucidating the pathogenic mechanisms of these diseases and deploy personalized treatments. Traditional and long-established model systems rarely reproduce either tissue complexity or human physiology faithfully; these shortcomings underscore the need for better models. Organoids represent a promising research model, helping us gain a more profound understanding of the digestive organs; this model can also be used to provide patients with precise and individualized treatment and to build rapid in vitro test models for drug screening or gene/cell therapy, linking basic research with clinical treatment. Over the past few decades, the use of organoids has led to an advanced understanding of the composition of each digestive organ and has facilitated disease modeling, chemotherapy dose prediction, CRISPR-Cas9 genetic intervention, high-throughput drug screening, and identification of SARS-CoV-2 targets, pathogenic infection. However, the existing organoids of the digestive system mainly include the epithelial system. In order to reveal the pathogenic mechanism of digestive diseases, it is necessary to establish a completer and more physiological organoid model. Combining organoids and advanced techniques to test individualized treatments of different formulations is a promising approach that requires further exploration. This review highlights the advancements in the field of organoid technology from the perspectives of disease modeling and personalized therapy.

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“…This differentiation recapitulates the key pancreatic developmental stages including definitive endoderm (DE), primitive gut tube (PGT), posterior foregut (PF), pancreatic progenitor (PP) and includes the intermediary pancreatic organoid (PO) expansion and final islet-like differentiation. The POs generated by this protocol can be frozen and thawed successfully (up to passage 15) ( Cujba et al., 2022 ) and can be used for long term-experiments, saving cost and time. All the steps underlined bellow are carried out in sterile and aseptic conditions using a Class II safety laminar flow cabinet.…”

Section: Before You Beginmentioning

confidence: 99%

“…Upon differentiation, organoids contained beta, delta, and alpha cells. For complete details on the use and execution of this protocol, please refer to Cujba et al. (2022) .…”

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Differentiation of beta-like cells from human induced pluripotent stem cell-derived pancreatic progenitor organoids

et al. 2022

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An HNF1α truncation associated with maturity-onset diabetes of the young impairs pancreatic progenitor differentiation by antagonizing HNF1β function

Cited by 23 publications

References 75 publications

Reduced calcium levels and accumulation of abnormal insulin granules in stem cell models of HNF1A deficiency

Reduced calcium levels and accumulation of abnormal insulin granules in stem cell models of HNF1A deficiency

Applications of human organoids in the personalized treatment for digestive diseases

Differentiation of beta-like cells from human induced pluripotent stem cell-derived pancreatic progenitor organoids

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