The Wnt/β‐catenin pathway determines the predisposition and efficiency of liver‐to‐pancreas reprogramming

Cohen, Helit; Barash, Hila; Meivar‐Levy, Irit; Molakandov, Kfir; Ben‐Shimon, Marina; Gurevich, Michael; Zoabi, Fatima; Har‐Zahav, Adi; Gebhardt, Rolf; Gaunitz, Frank; Mor, Eytan; Ravassard, Philippe; Greenberger, Shoshana; Ferber, Sarah

doi:10.1002/hep.29827

Cited by 17 publications

(28 citation statements)

References 44 publications

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“…Furthermore, overexpression of miR-690 decreased the protein levels of Sox9 and β-catenin (Fig. 6), indicating that this noncoding RNA may regulate the Wnt signaling pathway, which has been thoroughly investigated and is necessary for controlling the development of β-cells and their function [16, 28, 29]. These findings suggested that the important function of miR-690 during IPCs differentiation was predominantly regulated by the miR-690/Sox9 and β-catenin axes, confirming that the interactions of miRNAs and transcription factors were involved in the differentiation of mouse iPSCs to IPCs.…”

Section: Discussionmentioning

confidence: 99%

microRNA-690 regulates induced pluripotent stem cells (iPSCs) differentiation into insulin-producing cells by targeting Sox9

Huang

Guo

et al. 2019

Stem Cell Res Ther

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Background The regulatory mechanism of insulin-producing cells (IPCs) differentiation from induced pluripotent stem cells (iPSCs) in vitro is very important in the phylogenetics of pancreatic islets, the molecular pathogenesis of diabetes, and the acquisition of high-quality pancreatic β-cells derived from stem cells for cell therapy. Methods miPSCs were induced for IPCs differentiation. miRNA microarray assays were performed by using total RNA from our iPCs-derived IPCs containing undifferentiated iPSCs and iPSCs-derived IPCSs at day 4, day 14, and day 21 during step 3 to screen the differentially expressed miRNAs (DEmiRNAs) related to IPCs differentiation, and putative target genes of DEmiRNAs were predicted by bioinformatics analysis. miR-690 was selected for further research, and MPCs were transfected by miR-690-agomir to confirm whether it was involved in the regulation of IPCs differentiation in iPSCs. Quantitative Real-Time PCR (qRT-PCR), Western blotting, and immunostaining assays were performed to examine the pancreatic function of IPCs at mRNA and protein level respectively. Flow cytometry and ELISA were performed to detect differentiation efficiency and insulin content and secretion from iPSCs-derived IPCs in response to stimulation at different concentration of glucose. The targeting of the 3′-untranslated region of Sox9 by miR-690 was examined by luciferase assay. Results We found that miR-690 was expressed dynamically during IPCs differentiation according to the miRNA array results and that overexpression of miR-690 significantly impaired the maturation and insulinogenesis of IPCs derived from iPSCs both in vitro and in vivo. Bioinformatic prediction and mechanistic analysis revealed that miR-690 plays a pivotal role during the differentiation of IPCs by directly targeting the transcription factor sex-determining region Y (SRY)-box9. Furthermore, downstream experiments indicated that miR-690 is likely to act as an inactivated regulator of the Wnt signaling pathway in this process. Conclusions We discovered a previously unknown interaction between miR-690 and sox9 but also revealed a new regulatory signaling pathway of the miR-690/Sox9 axis during iPSCs-induced IPCs differentiation. Electronic supplementary material The online version of this article (10.1186/s13287-019-1154-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

microRNA-690 regulates induced pluripotent stem cells (iPSCs) differentiation into insulin-producing cells by targeting Sox9

Huang

Guo

et al. 2019

Stem Cell Res Ther

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“…Some tumor cells utilized glutamine to provide both nicotinamide adenine dinucleotide phosphate (NADPH) and carbon for lipid and glutathione biosynthesis as well as nitrogen for nucleotide biosynthesis, which was essential in controlling oxidative stress and supporting proliferation [33, 34]. Moreover, glutamine metabolism is also critical for liver-to-pancreas transdifferentiation, mature adipocyte inflammatory responses, and immunological cell functions [35–37]. And glutamine metabolism impacted epigenetic states as well as genome organization via α -KG, eventually altered cellular differentiation decisions [38].…”

Section: Glutamine Metabolismmentioning

confidence: 99%

Glutamine Metabolism Is Essential for Stemness of Bone Marrow Mesenchymal Stem Cells and Bone Homeostasis

Zhou

Yang

Chen

et al. 2019

Stem Cells International

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Skeleton has emerged as an endocrine organ which is both capable of regulating energy metabolism and being a target for it. Glutamine is the most bountiful and flexible amino acid in the body which provides adenosine 5′-triphosphate (ATP) demands for cells. Emerging evidences support that glutamine which acts as the second metabolic regulator after glucose exerts crucial roles in bone homeostasis at cellular level, including the lineage allocation and proliferation of bone mesenchymal stem cells (BMSCs), the matrix mineralization of osteoblasts, and the biosynthesis in chondrocytes. The integrated mechanism consisting of WNT, mammalian target of rapamycin (mTOR), and reactive oxygen species (ROS) signaling pathway in a glutamine-dependent pattern is responsible to regulate the complex intrinsic biological process, despite more extensive molecules are deserved to be elucidated in glutamine metabolism further. Indeed, dysfunctional glutamine metabolism enhances the development of degenerative bone diseases, such as osteoporosis and osteoarthritis, and glutamine or glutamine progenitor supplementation can partially restore bone defects which may promote treatment of bone diseases, although the mechanisms are not quite clear. In this review, we will summarize and update the latest research findings and clinical trials on the crucial regulatory roles of glutamine metabolism in BMSCs and BMSC-derived bone cells, also followed with the osteoclasts which are important in bone resorption.

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“…Though suggested as likely ductular in origin, Sox9 has subsequently been reported to be expressed at low levels in some periportal hepatocytes (representing ∼4.53% of the total hepatocyte population) [70]. This is in conflict with the perivenous transdifferentiation pattern seen in many studies [55].…”

Section: Polycistronic and Hierarchical Transcription Factorsmentioning

confidence: 97%

Molecular mechanisms of transcription factor mediated cell reprogramming: conversion of liver to pancreas

Wild

Tosh

2021

Biochemical Society Transactions

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Transdifferentiation is a type of cellular reprogramming involving the conversion of one differentiated cell type to another. This remarkable phenomenon holds enormous promise for the field of regenerative medicine. Over the last 20 years techniques used to reprogram cells to alternative identities have advanced dramatically. Cellular identity is determined by the transcriptional profile which comprises the subset of mRNAs, and therefore proteins, being expressed by a cell at a given point in time. A better understanding of the levers governing transcription factor activity benefits our ability to generate therapeutic cell types at will. One well-established example of transdifferentiation is the conversion of hepatocytes to pancreatic β-cells. This cell type conversion potentially represents a novel therapy in T1D treatment. The identification of key master regulator transcription factors (which distinguish one body part from another) during embryonic development has been central in developing transdifferentiation protocols. Pdx1 is one such example of a master regulator. Ectopic expression of vector-delivered transcription factors (particularly the triumvirate of Pdx1, Ngn3 and MafA) induces reprogramming through broad transcriptional remodelling. Increasingly, complimentary cell culture techniques, which recapitulate the developmental microenvironment, are employed to coax cells to adopt new identities by indirectly regulating transcription factor activity via intracellular signalling pathways. Both transcription factor-based reprogramming and directed differentiation approaches ultimately exploit transcription factors to influence cellular identity. Here, we explore the evolution of reprogramming and directed differentiation approaches within the context of hepatocyte to β-cell transdifferentiation focussing on how the introduction of new techniques has improved our ability to generate β-cells.

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The Wnt/β‐catenin pathway determines the predisposition and efficiency of liver‐to‐pancreas reprogramming

Cited by 17 publications

References 44 publications

microRNA-690 regulates induced pluripotent stem cells (iPSCs) differentiation into insulin-producing cells by targeting Sox9

microRNA-690 regulates induced pluripotent stem cells (iPSCs) differentiation into insulin-producing cells by targeting Sox9

Glutamine Metabolism Is Essential for Stemness of Bone Marrow Mesenchymal Stem Cells and Bone Homeostasis

Molecular mechanisms of transcription factor mediated cell reprogramming: conversion of liver to pancreas

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