A Network of microRNAs Acts to Promote Cell Cycle Exit and Differentiation of Human Pancreatic Endocrine Cells

Wen, Jia; Mulas, Francesca; Gaertner, Bjoern; Sui, Yinghui; Wang, Jinzhao; Matta, Ileana; Zeng, Chun; Vinckier, Nicholas; Wang, Allen; Nguyen-Ngoc, Kim-Vy; Chiou, Joshua; Kaestner, Klaus H.; Frazer, Kelly A.; Carrano, Andrea C.; Shih, Hung-Ping

doi:10.1016/j.isci.2019.10.063

Cited by 22 publications

(21 citation statements)

References 50 publications

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“…∆LAMA1Enh and ∆CRB2Enh clonal lines were derived by targeting H1 hESCs (male). Cells were maintained and differentiated as described with some modifications (Jin et al, 2019;Rezania et al, 2014). In brief, hESCs were cultured in mTeSR1 media (Stem Cell Technologies) and propagated by passaging cells every 3 to 4 days using Accutase (eBioscience) for enzymatic cell dissociation.…”

Section: Maintenance and Differentiation Of H1 Hescsmentioning

confidence: 99%

Pancreatic progenitor epigenome maps prioritize type 2 diabetes risk genes with roles in development

Geusz

Wang

Chiou

et al. 2020

Preprint

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Genetic variants associated with type 2 diabetes (T2D) risk affect gene regulation in metabolically relevant tissues, such as pancreatic islets. Here, we investigated contributions of regulatory programs active during pancreatic development to T2D risk.Generation of chromatin maps from developmental precursors throughout pancreatic differentiation of human embryonic stem cells (hESCs) identifies enrichment of T2D variants in pancreatic progenitor-specific stretch enhancers that are not active in islets.Genes associated with progenitor-specific stretch enhancers are predicted to regulate developmental processes, most notably tissue morphogenesis. Through gene editing in hESCs, we demonstrate that progenitor-specific enhancers harboring T2D-associated variants regulate cell polarity genes LAMA1 and CRB2. Knockdown of lama1 or crb2 in zebrafish embryos causes a defect in pancreas morphogenesis and impairs islet cell development. Together, our findings reveal that a subset of T2D risk variants specifically affects pancreatic developmental programs, suggesting that dysregulation of developmental processes can predispose to T2D. This work was supported by grant T32 GM008666 (R.J.G.), grant P30 DK064391 (K.J.), R01 DK068471 and U01 DK105541 (M.S., B.R.).

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Section: Maintenance and Differentiation Of H1 Hescsmentioning

confidence: 99%

Pancreatic progenitor epigenome maps prioritize type 2 diabetes risk genes with roles in development

Geusz

Wang

Chiou

et al. 2020

Preprint

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“…We found that the combined treatment of miR-127 + miR-709 (combination 3) induced the highest Pdx1 expression among the tested conditions in stage 1 (Figure 7B). Elevated miR-127 expression is reported to suppress β-cell proliferation and insulin secretion [52], on the one hand, but on the other, it stimulates pancreatic progenitor cell differentiation among endocrine cells [53]. Moreover, the overexpression of miR-127 is known to promote mesendoderm generation via nodal signaling [54].…”

Section: Discussionmentioning

confidence: 99%

Exosome-Mediated Differentiation of Mouse Embryonic Fibroblasts and Exocrine Cells into β-Like Cells and the Identification of Key miRNAs for Differentiation

Mandal

et al. 2020

Biomedicines

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Diabetes is a concerning health malady worldwide. Islet or pancreas transplantation is the only long-term treatment available; however, the scarcity of transplantable tissues hampers this approach. Therefore, new cell sources and differentiation approaches are required. Apart from the genetic- and small molecule-based approaches, exosomes could induce cellular differentiation by means of their cargo, including miRNA. We developed a chemical-based protocol to differentiate mouse embryonic fibroblasts (MEFs) into β-like cells and employed mouse insulinoma (MIN6)-derived exosomes in the presence or absence of specific small molecules to encourage their differentiation into β-like cells. The differentiated β-like cells were functional and expressed pancreatic genes such as Pdx1, Nkx6.1, and insulin 1 and 2. We found that the exosome plus small molecule combination differentiated the MEFs most efficiently. Using miRNA-sequencing, we identified miR-127 and miR-709, and found that individually and in combination, the miRNAs differentiated MEFs into β-like cells similar to the exosome treatment. We also confirmed that exocrine cells can be differentiated into β-like cells by exosomes and the exosome-identified miRNAs. A new differentiation approach based on the use of exosome-identified miRNAs could help people afflicted with diabetes

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“…miR-375 expression is also of pivotal importance in pancreas organogenesis [ 62 ] as well as during β cell in vitro differentiation of human-induced pluripotent stem cells [ 48 ] and of embryonic stem cells. Indeed, when overexpressed in human embryonic stem cell-derived pancreatic progenitors, miR-375 induced cell cycle exit and promoted endocrine cell differentiation; of note, such an effect was mainly observed in combination with additional β cell enriched miRNAs (let-7g, let-7a, miR-200a and miR-127), demonstrating the role of multiple miRNAs network in the resulting phenotype [ 63 ]. Collectively, these data provide evidence that miR-375 is essential for normal glucose homeostasis, β cell differentiation and turnover, as well as for adaptive β cell expansion in response to increasing insulin demand.…”

Section: Micrornas That Confer Robustness To β Cell Identity: Focumentioning

confidence: 99%

“…Of relevance, miR-7 is also differentially expressed in hIPSCs [ 63 ] and in human embryonic stem cells (hESCs) during differentiation toward β cell fate [ 67 ]. Importantly, induced overexpression of miR-7 during hESCs differentiation improved generation of mature pancreatic insulin-producing cells and revealed the critical role of miR-7 in the modulation of β cell differentiation.…”

Section: Micrornas That Confer Robustness To β Cell Identity: Focumentioning

confidence: 99%

The Landscape of microRNAs in βCell: Between Phenotype Maintenance and Protection

Grieco

Brusco

Licata

et al. 2021

IJMS

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Diabetes mellitus is a group of heterogeneous metabolic disorders characterized by chronic hyperglycaemia mainly due to pancreatic β cell death and/or dysfunction, caused by several types of stress such as glucotoxicity, lipotoxicity and inflammation. Different patho-physiological mechanisms driving β cell response to these stresses are tightly regulated by microRNAs (miRNAs), a class of negative regulators of gene expression, involved in pathogenic mechanisms occurring in diabetes and in its complications. In this review, we aim to shed light on the most important miRNAs regulating the maintenance and the robustness of β cell identity, as well as on those miRNAs involved in the pathogenesis of the two main forms of diabetes mellitus, i.e., type 1 and type 2 diabetes. Additionally, we acknowledge that the understanding of miRNAs-regulated molecular mechanisms is fundamental in order to develop specific and effective strategies based on miRNAs as therapeutic targets, employing innovative molecules.

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A Network of microRNAs Acts to Promote Cell Cycle Exit and Differentiation of Human Pancreatic Endocrine Cells

Cited by 22 publications

References 50 publications

Pancreatic progenitor epigenome maps prioritize type 2 diabetes risk genes with roles in development

Pancreatic progenitor epigenome maps prioritize type 2 diabetes risk genes with roles in development

Exosome-Mediated Differentiation of Mouse Embryonic Fibroblasts and Exocrine Cells into β-Like Cells and the Identification of Key miRNAs for Differentiation

The Landscape of microRNAs in βCell: Between Phenotype Maintenance and Protection

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