Human Fucci Pancreatic Beta Cell Lines: New Tools to Study Beta Cell Cycle and Terminal Differentiation

Carlier, Géraldine; Maugein, Alicia; Cordier, Corinne; Pechberty, Sèverine; Garfa-Traoré, Meriem; Martin, Patrick; Scharfmann, Raphaël; Albagli, Olivier

doi:10.1371/journal.pone.0108202

Cited by 13 publications

(18 citation statements)

References 44 publications

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“…Their results showed that the induction of advanced differentiation is correlated with the exit from the cell cycle of these cells (Carlier et al 2014). Our results showed that immature beta-cells actively transcribe proliferation-related genes and that a higher percentage of beta-cells from suckling and weaning rats could be found at S and G2/M phases of the cell cycle when compared with beta-cells from adult rats.…”

Section: Discussionsupporting

confidence: 48%

Transcriptome landmarks of the functional maturity of rat beta-cells, from lactation to adulthood

Larqué

Velasco

Barajas‐Olmos

et al. 2016

Journal of Molecular Endocrinology

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Research on the postnatal development of pancreatic beta-cells has become an important subject in recent years. Understanding the mechanisms that govern beta-cell postnatal maturation could bring new opportunities to therapeutic approaches for diabetes. The weaning period consists of a critical postnatal window for structural and physiologic maturation of rat beta-cells. To investigate transcriptome changes involved in the maturation of beta-cells neighboring this period, we performed microarray analysis in fluorescence-activated cell-sorted (FACS) beta-cell-enriched populations. Our results showed a variety of gene sets including those involved in the integration of metabolism, modulation of electrical activity, and regulation of the cell cycle that play important roles in the maturation process. These observations were validated using reverse hemolytic plaque assay, electrophysiological recordings, and flow cytometry analysis. Moreover, we suggest some unexplored pathways such as sphingolipid metabolism, insulin-vesicle trafficking, regulation of transcription/transduction by miRNA-30, trafficking proteins, and cell cycle proteins that could play important roles in the process mentioned above for further investigation. ResearchFunctional maturation of rat beta-cells c larqué and others 57:1

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Section: Discussionsupporting

confidence: 48%

Transcriptome landmarks of the functional maturity of rat beta-cells, from lactation to adulthood

Larqué

Velasco

Barajas‐Olmos

et al. 2016

Journal of Molecular Endocrinology

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“…Moreover, EndoC‐βH2 cells have recently been used to develop a third generation of human β‐cell line stably expressing a CRE‐ER chimera, hence undergoing oncogene excision upon tamoxifen treatment . EndoC‐βH2 cells were also used as a basis to develop additional tools, such as the human fucci pancreatic β‐cell line, which allows the study of human β‐cell cycle and terminal differentiation, and by using this we can try to understand why human β‐cells are so reluctant to proliferate …”

Section: Human β‐Cell Sourcesmentioning

confidence: 99%

Mass production of functional human pancreatic β‐cells: why and how?

Scharfmann

Didiesheim

Richards

et al. 2016

Diabetes Obesity Metabolism

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).Diabetes (either type 1 or type 2) is due to insufficient functional β-cell mass. Research has, therefore, aimed to discover new ways to maintain or increase either β-cell mass or function.For this purpose, rodents have mainly been used as model systems and a large number of discoveries have been made. Meanwhile, although we have learned that rodent models represent powerful systems to model β-cell development, function and destruction, we realize that there are limitations when attempting to transfer the data to what is occurring in humans. Indeed, while human β-cells share many similarities with rodent β-cells, they also differ on a number of important parameters. In this context, developing ways to study human β-cell development, function and death represents an important challenge. This review will describe recent data on the development and use of convenient sources of human β-cells that should be useful tools to discover new ways to modulate functional β-cell mass in humans. K E Y W O R D Sβ-cells, β-cell lines, GPR68, human, pancreatic, RFX6, stem cells | INTRODUCTIONβ-Cells are rare specialized cells devoted to produce large amounts of insulin that is stored within granules and secreted in a tightly regulated fashion. 1 In the pancreas, β-cells are clustered, forming micro-organs, named the islets of Langerhans. A human pancreas contains around 1 million islets and each islet contains hundreds of β-cells. 2 Due to their stochastic spatial distribution, imaging human pancreatic islets in vivo remains extremely challenging. 3 Human islet purification from cadaveric donors is possible, but quantitatively limited, with major variation in terms of purity from one preparation to another. 4 In the past, we have learned a lot about β-cells using animal models, primarily rat and mouse.In such species, islets can be prepared from which β-cells are purified and studied in great detail. By performing comparative analyses, however, we have learned that while rodent and human β-cells share many similarities, they also differ on a number of important parameters. 5,6 In this context, developing ways to analyse human β-cells in great detail currently represents a major challenge.In this review, we will summarize our knowledge on similarities and differences between rodent and human β-cells. We will next concentrate on the different human β-cell sources that can be used to study this specific cell type. | SIMILARITIES AND DIFFERENCES BETWEEN RODENT AND HUMAN β-CELLSPancreatic β-cells can be considered as factories whose major task is to produce huge amounts of insulin (more than 20% of β-cell mRNA codes for insulin) 7 that is stored and secreted upon specific stimulation. During the past years, we have learned that while rodent β-cells represent an extremely useful model to approximate human β-cells, more remains to be learned by directly working on human β-cells. Indeed, rodent and human β-cells share many similarities, but also a number of differences. As a first example, two genes encode insulin in rodents (both rats...

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“…If one estimates that 20–40% of β-cells were actively engaged in the cell cycle (Figs. 5 and 6); that half of these labeled cells represent new daughter cells and the other half represent the residual parent cells; that adenovirus transduction leads to cyclin/cdks expression after 24 h, leaving 4 days for β-cells to divide; and that, after replication, β-cells will divide only once during the 5 days of the experiment (25,46–48), one can estimate that the yield of new daughter cells should be in the range of 30%. This is not dissimilar from the 29.6% increase in β-cell mass with the combination of early and late cyclins and cdks.…”

Section: Discussionmentioning

confidence: 99%

Early and Late G1/S Cyclins and Cdks Act Complementarily to Enhance Authentic Human β-Cell Proliferation and Expansion

et al. 2015

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β-Cell regeneration is a key goal of diabetes research. Progression through the cell cycle is associated with retinoblastoma protein (pRb) inactivation via sequential phosphorylation by the “early” cyclins and cyclin-dependent kinases (cdks) (d-cyclins cdk4/6) and the “late” cyclins and cdks (cyclin A/E and cdk1/2). In β-cells, activation of either early or late G1/S cyclins and/or cdks is an efficient approach to induce cycle entry, but it is unknown whether the combined expression of early and late cyclins and cdks might have synergistic or additive effects. Thus, we explored whether a combination of both early and late cyclins and cdks might more effectively drive human β-cell cell cycle entry than either group alone. We also sought to determine whether authentic replication with the expansion of adult human β-cells could be demonstrated. Late cyclins and cdks do not traffic in response to the induction of replication by early cyclins and cdks in human β-cells but are capable of nuclear translocation when overexpressed. Early plus late cyclins and cdks, acting via pRb phosphorylation on distinct residues, complementarily induce greater proliferation in human β-cells than either group alone. Importantly, the combination of early and late cyclins and cdks clearly increased human β-cell numbers in vitro. These findings provide additional insight into human β-cell expansion. They also provide a novel tool for assessing β-cell expansion in vitro.

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Human Fucci Pancreatic Beta Cell Lines: New Tools to Study Beta Cell Cycle and Terminal Differentiation

Cited by 13 publications

References 44 publications

Transcriptome landmarks of the functional maturity of rat beta-cells, from lactation to adulthood

Transcriptome landmarks of the functional maturity of rat beta-cells, from lactation to adulthood

Mass production of functional human pancreatic β‐cells: why and how?

Early and Late G1/S Cyclins and Cdks Act Complementarily to Enhance Authentic Human β-Cell Proliferation and Expansion

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