Point mutations in the PDX1 transactivation domain impair human β-cell development and function

Wang, Xianming; Sterr, Michael; Ansarullah,; Burtscher, Ingo; Böttcher, Anika; Beckenbauer, Julia; Siehler, Johanna; Meitinger, Thomas; Häring, Hans‐Ulrich; Staiger, Harald; Cernilogar, Filippo M.; Schotta, Gunnar; Irmler, Martin; Beckers, Johannes; Wright, Christopher V.E.; Bakhti, Mostafa; Lickert, Heiko

doi:10.1016/j.molmet.2019.03.006

Cited by 75 publications

(69 citation statements)

References 59 publications

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“…It is reported that mutations of PDX1 could lead to insulin secretion defect [30][31][32]. Similarly, insu ciency of PDX1 expression in pancreatic β-cells in animal models also accounted for pancreatic βcell impairment and T2D [13].…”

Section: Discussionmentioning

confidence: 97%

miR-765 Impairs Pancreatic β-cell Function by Targeting PDX1 in type 2 Diabetes

Li¹,

Wang²,

Li³

et al. 2020

Preprint

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Background: Type 2 diabetes (T2D) is highly connected with the defect in insulin secretion of pancreatic β-cells, which has been developing into a severe public health problem.Methods: Here, we first detected expression of PDX1 and miR-765 in peripheral blood from 40 patients with T2D and 40 healthy volunteers. INS-1E cells (pancreatic β-cell line) were cultured as experimental model. For glucose induction, we incubated INS-1E cells with 11 mM glucose as control group and INS-1E cells with 25 mM glucose as T2D model group. For target relationship verification, we performed Luciferase reporter assay. Generally, we utilized qRT-PCR (quantitative real-time PCR), western blotting, insulin secretion detection, CCK-8, and flow cytometry in this study.Results: The expression level of PDX1 was dramatically lower in peripheral blood from T2D patients than healthy volunteers, while miR-765 exhibited an opposite result. PDX1 expression level had an inverse correlation with blood glucose level of T2D patients whereas miR-765 exhibited a positive correlation. Furthermore, PDX1 improved insulin secretion, cell viability, and restrained cell apoptosis of INS-1E cells. PDX1 was identified as a target of miR-765 which was observed to reduce insulin secretion, cell viability, and induce cell apoptosis of INS-1E cells.Conclusions: Taken together, we confirmed that miR-765 could cause detrimental effect on pancreatic β-cell survival and function by targeting and repressing PDX1 in T2D.

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Section: Discussionmentioning

confidence: 97%

miR-765 Impairs Pancreatic β-cell Function by Targeting PDX1 in type 2 Diabetes

Li¹,

Wang²,

Li³

et al. 2020

Preprint

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“…These are currently being explored for cell replacement therapy, as these cells can spontaneously differentiate into SC-β cells after transplantation over the course of months [3,[27][28][29], but the mechanism of this maturation process is unknown and differs based on rodent species [27]. SC-β cells or earlier progenitors, particularly derived from diabetic patients through an induced pluripotent stem cell (iPSC) intermediate, are currently being studied for disease modeling and drug screening purposes [3,[30][31][32][33][34][35][36][37][38][39][40][41]. These studies would benefit from a cellular assembly that more closely reflects the native islet microenvironment [42].…”

Section: Discussionmentioning

confidence: 99%

Hydrogel platform for in vitro three-dimensional assembly of human stem cell-derived β cells and endothelial cells

Augsornworawat¹,

Velazco-Cruz²,

Song³

et al. 2019

Preprint

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Differentiation of stem cells into functional replacement cells and tissues is a major goal of the regenerative medicine field. However, one limitation has been organization of differentiated cells into multi-cellular, three-dimensional assemblies. The islets of Langerhans contain many endocrine and non-endocrine cell types, such as insulin-producing β cells and endothelial cells. Transplantation of exogenous islets into diabetic patients can serve as a cell replacement therapy, replacing the need for patients to inject themselves with insulin, but the number of available islets from cadaveric donors is low. We have developed a strategy of assembling human embryonic stem cell-derived β cells with endothelial cells into three-dimensional aggregates on a hydrogel. The resulting islet organoids express β cell markers and are functional, capable of undergoing glucose-stimulated insulin secretion. These results provide a platform for evaluating the effects of the islet tissue microenvironment on human embryonic stem cell-derived β cells and other islet endocrine cells to develop tissue engineered islets.

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“…The clinical presentation of mutations in pancreatic transcription factors can vary according to the severity of the mutations and, for PDX1, cases presenting as isolated permanent neonatal diabetes mellitus without [34] or with subclinical exocrine insufficiency [35] have been reported. Interestingly, monoallelic loss of PDX1 has a strong, negative impact on the generation of insulin-positive beta-like cells from hPSCs during in vitro differentiation [18,36]. This finding is intriguing as mice that are haploinsufficient for Pdx1 are reported to develop normally [12,13], but become diabetic with age due to decreased beta cell function [37,38] and increased beta cell apoptosis [39,40].…”

Section: Models To Study the Role Of Transcription Factors In Human Pmentioning

confidence: 99%

Transcription factors that shape the mammalian pancreas

2020

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Improving our understanding of mammalian pancreas development is crucial for the development of more effective cellular therapies for diabetes. Most of what we know about mammalian pancreas development stems from mouse genetics. We have learnt that a unique set of transcription factors controls endocrine and exocrine cell differentiation. Transgenic mouse models have been instrumental in studying the function of these transcription factors. Mouse and human pancreas development are very similar in many respects, but the devil is in the detail. To unravel human pancreas development in greater detail, in vitro cellular models (including directed differentiation of stem cells, human beta cell lines and human pancreatic organoids) are used; however, in vivo validation of these results is still needed. The current best ‘model’ for studying human pancreas development are individuals with monogenic forms of diabetes. In this review, we discuss mammalian pancreas development, highlight some discrepancies between mouse and human, and discuss selected transcription factors that, when mutated, cause permanent neonatal diabetes.

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Point mutations in the PDX1 transactivation domain impair human β-cell development and function

Cited by 75 publications

References 59 publications

miR-765 Impairs Pancreatic β-cell Function by Targeting PDX1 in type 2 Diabetes

miR-765 Impairs Pancreatic β-cell Function by Targeting PDX1 in type 2 Diabetes

Hydrogel platform for in vitro three-dimensional assembly of human stem cell-derived β cells and endothelial cells

Transcription factors that shape the mammalian pancreas

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