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Pancreatic beta-cells: From generation to regeneration.
Get PDFThe pancreas is composed of two main compartments consisting of endocrine and exocrine tissues. The majority of the organ is exocrine and responsible for the synthesis of digestive enzymes and for their transport via an intricate ductal system into the duodenum. The endocrine tissue represents less than 2% of the organ and is organized into functional units called islets of Langerhans, comprising alpha-, beta-, delta-, epsilon- and PP-cells, producing the hormones glucagon, insulin, somatostatin, ghrelin and pancreatic polypeptide (PP), respectively. Insulin-producing beta-cells play a central role in the control of the glucose homeostasis. Accordingly, absolute or relative deficiency in beta-cells may ultimately lead to type 1 and/or type 2 diabetes, respectively. One major goal of diabetes research is therefore to understand the molecular mechanisms controlling the development of beta-cells during pancreas morphogenesis, but also those underlying the regeneration of adult injured pancreas, and assess their significance for future cell-based therapy. In this review, we will therefore present new insights into beta-cell development with focus on beta-cell regeneration
A genetic mouse model for progressive ablation and regeneration of insulin producing beta-cells
No full text<div><p>The putative induction of adult β-cell regeneration represents a promising approach for the treatment of type 1 diabetes. Toward this ultimate goal, it is essential to develop an inducible model mimicking the long-lasting disease progression. In the current study, we have established a novel β-cell ablation mouse model, in which the β-cell mass progressively declines, as seen in type 1 diabetes. The model is based on the β-cell specific genetic ablation of the transcription initiation factor 1A, TIF-IA, essential for RNA Polymerase I activity (TIF-IA<sup>Δ/Δ</sup>). Using this approach, we induced a slow apoptotic response that eventually leads to a protracted β-cell death. In this model, we observed β-cell regeneration that resulted in a complete recovery of the β-cell mass and normoglycemia. In addition, we showed that adaptive proliferation of remaining β-cells is the prominent mechanism acting to compensate for the massive β-cell loss in young but also aged mice. Interestingly, at any age, we also detected β-like cells expressing the glucagon hormone, suggesting a transition between α- and β-cell identities or <i>vice versa</i>. Taken together, the TIF-IA<sup>Δ/Δ</sup> mouse model can be used to investigate the potential therapeutic approaches for type 1 diabetes targeting β-cell regeneration.</p></div
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Forcing alpha-cell-mediated beta-cell regeneration
No full textLe diabète de type 1 (DT1) résulte de la destruction des cellules β productrices d’insuline par le système immunitaire. Cette condition représente un enjeu de santé publique majeur car, malgré les thérapies actuelles, les patients atteints développent trop souvent des complications cardio-vasculaires. Des thérapies alternatives se doivent donc d’être mises au point. Ainsi, diverses approches visent à reprogrammer/différencier (in vitro ou in vivo) différents types cellulaires pancréatiques afin de générer des cellules β (productrices d’insuline) fonctionnelles. Dans ce but, notre laboratoire a notamment montré que les cellules α (productrices de glucagon) embryonnaires peuvent être régénérées et converties en cellules β fonctionnelles par l’expression ectopique du seul gène Pax4 (un gène normalement impliqué dans la spécification embryonnaire du lignage β - (Collombat and Mansouri, 2009)). Dans la première partie de ce travail, nous démontrons que les cellules α à l’âge adulte (Al-Hasani et al., 2013) retiennent leur capacité de régénération et de conversion en cellules β, celles-ci étant fonctionnelles et capable de remplacer plusieurs fois l’ensemble des cellules β du pancréas. Cependant, cette approche transgénique serait difficile à mettre en œuvre chez l’homme. De nombreux cribles furent donc initiées dans le but de trouver des petites molécules/composés chimiques mimant les effets de Pax4. Un composé potentiel, GABA, fut ainsi identifié et caractérisé.Type 1 diabetes (T1D) results from the destruction of insulin-producing β-cells by the immune system. This condition is a major public health issue because, despite current therapies, patients often develop cardiovascular complications. Therefore alternative therapies need to be developed. Thus, various approaches are designed to reprogram / differentiate (in vitro or in vivo) different pancreatic cell types to generate functional (insulin-producing) β-cells. To this end, our laboratory has shown that especially the embryonic α-cells (producing glucagon) can be regenerated and converted into functional β-cells by the ectopic expression of the Pax4 gene (usually a gene involved in the specification of embryonic lineage β - (Collombat and Mansouri, 2009)). In the first part of this work, we show that α-cells in adulthood (Al-Hasani et al., 2013) retain their capacity for regeneration and conversion into β-cells, the latter being functional and able to replace repeatedly all the β-cells of the pancreas. However, this transgenic approach would be difficult to implement in humans. Many screens were therefore initiated in order to find small molecules / chemical compounds that mimic the effects of Pax4. A potential compound, GABA, was identified and characterized. Our results demonstrate that treatment of WT mice with GABA results in a significant increase in the number and size of the islets (caused by insulin+ cell hyperplasia). By using lineage tracing tools, our results indicate that these "β-like" neo-generated cells are coming from glucagon+ cells
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Conversion of gastrointestinal somatostatin-expressing D cells into insulin-producing β-like cells upon Pax4 misexpression
No full textLe diabète est l'une des maladies métaboliques les plus répandues dans le monde. Différents types de diabète ont été décrits comme le diabète de type 1, de type 2 et monogénique. Le diabète de type 1 résulte de la perte auto-immune des cellules β productrices d'insuline. Il est important de souligner que malgré les thérapies actuelles, les personnes diabétiques de type 1 présentent encore une qualité de vie considérablement altérée et une espérance de vie réduite. Il subsiste donc un fort besoin en thérapies alternatives. Une piste de recherche d'un grand intérêt est la régénération des cellules β par conversion de cellules endogènes en cellules productrices d'insuline.Des résultats antérieurs de notre laboratoire ont démontré que l'expression ectopique de Pax4 dans les cellules β pancréatiques productrices de somatostatine induit leur néo-genèse et leur conversion en cellules β. Fait intéressant, le tractus gastro-intestinal contient un grand nombre de cellules D exprimant la somatostatine. L’on pourrait donc se demander si telle conversion médiée par Pax4 pourrait également déclencher la transformation des cellules D intestinales en cellules β.Dans ce but, nous avons généré des souris transgéniques exprimant Pax4 dans les cellules productrices de somatostatine et nous avons analysé le duodénum et l'estomac. De plus, nous avons également mis en œuvre une approche ex vivo basée sur des organoïdes intestinaux dérivés de souris.Nos résultats démontrent la présence de cellules insuline+ dans les tissus gastro-intestinaux analysés, et par le traçage de lignage, il apparait que ces cellules proviennent de cellules D. Une caractérisation plus poussée des cellules productrices d’insuline résultantes montre qu'elles expriment plusieurs marqueurs de cellules β. De plus, nous avons évalué la fonctionnalité de ces cellules néo-générées au moyen d'organoïdes intestinaux. Les résultats obtenus prouvent la capacité des organoïdes transgéniques à libérer de l'insuline en réponse à une stimulation par le glucose.Ainsi, nos résultats suggèrent que la seule expression ectopique de Pax4 dans les cellules D les convertit en cellules de type β. De plus, ces cellules d'insuline+ néo-générées sont fonctionnelles, ce qui ouvre la porte vers de nouvelles recherches d’intérêt pour le diabète de type 1.Diabetes is one of the most common metabolic diseases worldwide. Different types of diabetes have been described such as type 1, type 2 and monogenic diabetes. Type 1 diabetes results from the autoimmune-mediated loss of insulin-producing β-cells. Importantly, despite currently available therapies, type 1 diabetic individuals still exhibit a significantly altered quality of life and a shortened life expectancy. There is therefore a need for the establishment of alternative therapies. One research avenue of great interest is the regeneration of lost β-cells by converting endogenous cells into insulin-producing cells.Previous results from our laboratory demonstrated that the ectopic expression of Pax4 in pancreatic somatostatin-producing β-cells triggers their neogenesis and subsequent conversion into β-like cells. Interestingly, the gastrointestinal tract contains a great number of somatostatin-expressing D cells. One could therefore wonder whether such Pax4-mediated conversion could also trigger D cells to be turned into β-like cells. Towards this goal, we generated transgenic mice misexpressing Pax4 in somatostatin cells and we analysed the duodenum and the stomach. Moreover, we also implemented an ex vivo approach based on mice-derived gut organoids.Our results outlined the presence of insulin+ cells in the gastrointestinal tissues analysed, and by lineage tracing, we proved that these cells arose from D cells. Further characterisation of the insulin-converted cells demonstrated that they expressed several β-cell markers. Additionally, we assessed the functionality of these neo-generated β-like cells by means of gut organoids. The results obtained proved the capacity of transgenic organoids to release insulin upon glucose stimulation.Hence, our results suggest that the sole misexpression of Pax4 in D cells converts these into β-like cells. Further, we confirmed that these gastrointestinal neo-generated insulin+ cells are functional, thus opening new research avenues in the context of diabetes research
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