24 results on '"De Groef S"'
Search Results
2. Genome-wide analysis identifies Homothorax and Extradenticle as regulators of insulin in Drosophila Insulin-Producing cells
- Author
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Winant, M., primary, Buhler, K., additional, Clements, J., additional, De Groef, S., additional, Hens, K., additional, Vulsteke, V, additional, and Callaerts, P., additional
- Published
- 2022
- Full Text
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3. Making β(-like)-cells from exocrine pancreas
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Staels, W., primary, De Groef, S., additional, Bussche, L., additional, Leuckx, G., additional, Van de Casteele, M., additional, De Leu, N., additional, Baeyens, L., additional, Heremans, Y., additional, and Heimberg, H., additional
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- 2016
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4. STAT3 modulates β-cell cycling in injured mouse pancreas and protects against DNA damage
- Author
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De Groef, S, primary, Renmans, D, additional, Cai, Y, additional, Leuckx, G, additional, Roels, S, additional, Staels, W, additional, Gradwohl, G, additional, Baeyens, L, additional, Heremans, Y, additional, Martens, G A, additional, De Leu, N, additional, Sojoodi, M, additional, Van de Casteele, M, additional, and Heimberg, H, additional
- Published
- 2016
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5. Accessory cells for β-cell transplantation
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Staels, W., primary, De Groef, S., additional, Heremans, Y., additional, Coppens, V., additional, Van Gassen, N., additional, Leuckx, G., additional, Van de Casteele, M., additional, Van Riet, I., additional, Luttun, A., additional, Heimberg, H., additional, and De Leu, N., additional
- Published
- 2015
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6. Neurogenin 3(+) cells contribute to beta-cell neogenesis and proliferation in injured adult mouse pancreas
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Van de Casteele, M., Leuckx, G., Baeyens, L., Cai, Y., Yuchi, Y., Coppens, V., De Groef, S., Eriksson, Maria, Svensson, Christoffer, Ahlgren, Ulf, Ahnfelt-Ronne, J., Madsen, O. D., Waisman, A., Dor, Y., Jensen, J. N., Heimberg, H., Van de Casteele, M., Leuckx, G., Baeyens, L., Cai, Y., Yuchi, Y., Coppens, V., De Groef, S., Eriksson, Maria, Svensson, Christoffer, Ahlgren, Ulf, Ahnfelt-Ronne, J., Madsen, O. D., Waisman, A., Dor, Y., Jensen, J. N., and Heimberg, H.
- Abstract
We previously showed that injury by partial duct ligation (PDL) in adult mouse pancreas activates Neurogenin 3 (Ngn3)(+) progenitor cells that can differentiate to beta cells ex vivo. Here we evaluate the role of Ngn3(+) cells in beta cell expansion in situ. PDL not only induced doubling of the beta cell volume but also increased the total number of islets. beta cells proliferated without extended delay (the so-called 'refractory' period), their proliferation potential was highest in small islets, and 86% of the beta cell expansion was attributable to proliferation of pre-existing beta cells. At sufficiently high Ngn3 expression level, upto 14% of all beta cells and 40% of small islet beta cells derived from non-beta cells. Moreover, beta cell proliferation was blunted by a selective ablation of Ngn3(+) cells but not by conditional knockout of Ngn3 in pre-existing beta cells supporting a key role for Ngn3(+) insulin(-) cells in beta cell proliferation and expansion. We conclude that Ngn3(+) cell-dependent proliferation of pre-existing and newly-formed beta cells as well as reprogramming of non-beta cells contribute to in vivo beta cell expansion in the injured pancreas of adult mice.
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- 2013
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7. Neurogenin 3+ cells contribute to β-cell neogenesis and proliferation in injured adult mouse pancreas
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Van de Casteele, M, primary, Leuckx, G, additional, Baeyens, L, additional, Cai, Y, additional, Yuchi, Y, additional, Coppens, V, additional, De Groef, S, additional, Eriksson, M, additional, Svensson, C, additional, Ahlgren, U, additional, Ahnfelt-Rønne, J, additional, Madsen, O D, additional, Waisman, A, additional, Dor, Y, additional, Jensen, J N, additional, and Heimberg, H, additional
- Published
- 2013
- Full Text
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8. Accessory cells for β-cell transplantation.
- Author
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Staels, W., De Groef, S., Heremans, Y., Coppens, V., Van Gassen, N., Leuckx, G., Van de Casteele, M., Van Riet, I., Luttun, A., Heimberg, H., and De Leu, N.
- Subjects
- *
ANTIGEN presenting cells , *B cells , *TREATMENT of diabetes , *INSULIN therapy , *ARTIFICIAL pancreases , *GLYCEMIC control , *ISLANDS of Langerhans , *THERAPEUTICS - Abstract
Despite recent advances, insulin therapy remains a treatment, not a cure, for diabetes mellitus with persistent risk of glycaemic alterations and life-threatening complications. Restoration of the endogenous β-cell mass through regeneration or transplantation offers an attractive alternative. Unfortunately, signals that drive β-cell regeneration remain enigmatic and β-cell replacement therapy still faces major hurdles that prevent its widespread application. Co-transplantation of accessory non-islet cells with islet cells has been shown to improve the outcome of experimental islet transplantation. This review will highlight current travails in β-cell therapy and focuses on the potential benefits of accessory cells for islet transplantation in diabetes. [ABSTRACT FROM AUTHOR]
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- 2016
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9. Reference genes to study the sex-biased expression of genes regulating Drosophila metabolism.
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De Groef S, Ribeiro Lopes M, Winant M, Rosschaert E, Wilms T, Bolckmans L, Calevro F, and Callaerts P
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- Animals, Female, Male, Gene Expression Regulation, Gene Expression Profiling methods, Reference Standards, Drosophila Proteins genetics, Drosophila Proteins metabolism, Drosophila melanogaster genetics, Drosophila melanogaster metabolism, Drosophila genetics, Drosophila metabolism, Genes, Insect, Sex Characteristics
- Abstract
Sex is an important variable in biology. Notable differences have been observed between male and female Drosophila in regulation of metabolism, in response to nutritional challenges, and in phenotypes relevant for obesity and metabolic disorders. The differences between males and females can be expected to result from differences in gene expression. We observed that expression levels of reference genes commonly used for normalization of qRT-PCR results such as GAPDH, β-actin, and 18SrRNA, show prominent sexual dimorphism. Since this will impact relative expression and conclusions related to that, we performed a systematic analysis of candidate reference genes with the objective of identifying reference genes with stable expression in male and female Drosophila. These reference genes (LamCa, βTub60D and βTub97EF) were then used to assess sex-specific differences in expression of metabolism associated genes. Additionally, we evaluated the utility of these reference genes following a nutritional challenge and showed that LamCa and βtub97EF are stably expressed between sexes and under different nutritional conditions and are thus suitable as reference genes. Our results highlight the importance of evaluating the stability of reference genes when sex-specific differences in gene expression are studied, and identify structural genes as a category worth exploring as reference genes in other species. Finally, we also uncovered hitherto unknown sexually dimorphic expression of a number of metabolism-associated genes, information of interest to others working in the field of metabolic disorders., (© 2024. The Author(s).)
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- 2024
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10. Genome-wide analysis identifies Homothorax and Extradenticle as regulators of insulin in Drosophila Insulin-Producing cells.
- Author
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Winant M, Buhler K, Clements J, De Groef S, Hens K, Vulsteke V, and Callaerts P
- Subjects
- Animals, Drosophila melanogaster genetics, Drosophila melanogaster metabolism, Genome-Wide Association Study, Insulin genetics, Insulin metabolism, Transcription Factors genetics, Transcription Factors metabolism, Drosophila genetics, Drosophila metabolism, Drosophila Proteins metabolism
- Abstract
Drosophila Insulin-Producing Cells (IPCs) are the main production site of the Drosophila Insulin-like peptides or dilps which have key roles in regulating growth, development, reproduction, lifespan and metabolism. To better understand the signalling pathways and transcriptional networks that are active in the IPCs we queried publicly available transcriptome data of over 180 highly inbred fly lines for dilp expression and used dilp expression as the input for a Genome-wide association study (GWAS). This resulted in the identification of variants in 125 genes that were associated with variation in dilp expression. The function of 57 of these genes in the IPCs was tested using an RNAi-based approach. We found that IPC-specific depletion of most genes resulted in differences in expression of one or more of the dilps. We then elaborated further on one of the candidate genes with the strongest effect on dilp expression, Homothorax, a transcription factor known for its role in eye development. We found that Homothorax and its binding partner Extradenticle are involved in regulating dilp2, -3 and -5 expression and that genetic depletion of both TFs shows phenotypes associated with reduced insulin signalling. Furthermore, we provide evidence that other transcription factors involved in eye development are also functional in the IPCs. In conclusion, we showed that this expression level-based GWAS approach identified genetic regulators implicated in IPC function and dilp expression., Competing Interests: The authors have declared that no competing interests exist.
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- 2022
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11. Sexual Dimorphism in Metabolic Responses to Western Diet in Drosophila melanogaster .
- Author
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De Groef S, Wilms T, Balmand S, Calevro F, and Callaerts P
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- Animals, Diet, Western, Drosophila, Female, Humans, Male, Obesity, Drosophila melanogaster metabolism, Sex Characteristics
- Abstract
Obesity is a chronic disease affecting millions of people worldwide. The fruit fly ( Drosophila melanogaster ) is an interesting research model to study metabolic and transcriptomic responses to obesogenic diets. However, the sex-specific differences in these responses are still understudied and perhaps underestimated. In this study, we exposed adult male and female Dahomey fruit flies to a standard diet supplemented with sugar, fat, or a combination of both. The exposure to a diet supplemented with 10% sugar and 10% fat efficiently induced an increase in the lipid content in flies, a hallmark for obesity. This increase in lipid content was more prominent in males, while females displayed significant changes in glycogen content. A strong effect of the diets on the ovarian size and number of ma-ture oocytes was also present in females exposed to diets supplemented with fat and a combina-tion of fat and sugar. In both males and females, fat body morphology changed and was associ-ated with an increase in lipid content of fat cells in response to the diets. The expression of me-tabolism-related genes also displayed a strong sexually dimorphic response under normal condi-tions and in response to sugar and/or fat-supplemented diets. Here, we show that the exposure of adult fruit flies to an obesogenic diet containing both sugar and fat allowed studying sexual dimorphism in metabolism and the expression of genes regulating metabolism.
- Published
- 2021
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12. Retraction Note: Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice.
- Author
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Baeyens L, Lemper M, Leuckx G, De Groef S, Bonfanti P, Stangé G, Shemer R, Nord C, Scheel DW, Pan FC, Ahlgren U, Gu G, Stoffers DA, Dor Y, Ferrer J, Gradwohl G, Wright CVE, Van de Casteele M, German MS, Bouwens L, and Heimberg H
- Abstract
This article has been retracted; see accompanying Retraction Note, which can be accessed via a link at the top of the paper.
- Published
- 2020
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13. Vegf-A mRNA transfection as a novel approach to improve mouse and human islet graft revascularisation.
- Author
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Staels W, Verdonck Y, Heremans Y, Leuckx G, De Groef S, Heirman C, de Koning E, Gysemans C, Thielemans K, Baeyens L, Heimberg H, and De Leu N
- Subjects
- Animals, Cell Survival, Humans, Insulin metabolism, Insulin-Secreting Cells transplantation, Islets of Langerhans Transplantation, Mice, Insulin-Secreting Cells cytology, Islets of Langerhans cytology, Neovascularization, Physiologic, RNA, Messenger genetics, Transfection, Vascular Endothelial Growth Factor A genetics
- Abstract
Aims/hypothesis: The initial avascular period following islet transplantation seriously compromises graft function and survival. Enhancing graft revascularisation to improve engraftment has been attempted through virus-based delivery of angiogenic triggers, but risks associated with viral vectors have hampered clinical translation. In vitro transcribed mRNA transfection circumvents these risks and may be used for improving islet engraftment., Methods: Mouse and human pancreatic islet cells were transfected with mRNA encoding the angiogenic growth factor vascular endothelial growth factor A (VEGF-A) before transplantation under the kidney capsule in mice., Results: At day 7 post transplantation, revascularisation of grafts transfected with Vegf-A (also known as Vegfa) mRNA was significantly higher compared with non-transfected or Gfp mRNA-transfected controls in mouse islet grafts (2.11- and 1.87-fold, respectively) (vessel area/graft area, mean ± SEM: 0.118 ± 0.01 [n = 3] in Vegf-A mRNA transfected group (VEGF) vs 0.056 ± 0.01 [n = 3] in no RNA [p < 0.05] vs 0.063 ± 0.02 [n = 4] in Gfp mRNA transfected group (GFP) [p < 0.05]); EndoC-bH3 grafts (2.85- and 2.48-fold. respectively) (0.085 ± 0.02 [n = 4] in VEGF vs 0.030 ± 0.004 [n = 4] in no RNA [p < 0.05] vs 0.034 ± 0.01 [n = 5] in GFP [p < 0.05]); and human islet grafts (3.17- and 3.80-fold, respectively) (0.048 ± 0.013 [n = 3] in VEGF vs 0.015 ± 0.0051 [n = 4] in no RNA [p < 0.01] vs 0.013 ± 0.0046 [n = 4] in GFP [p < 0.01]). At day 30 post transplantation, human islet grafts maintained a vascularisation benefit (1.70- and 1.82-fold, respectively) (0.049 ± 0.0042 [n = 8] in VEGF vs 0.029 ± 0.0052 [n = 5] in no RNA [p < 0.05] vs 0.027 ± 0.0056 [n = 4] in GFP [p < 0.05]) and a higher beta cell volume (1.64- and 2.26-fold, respectively) (0.0292 ± 0.0032 μl [n = 7] in VEGF vs 0.0178 ± 0.0021 μl [n = 5] in no RNA [p < 0.01] vs 0.0129 ± 0.0012 μl [n = 4] in GFP [p < 0.001])., Conclusions/interpretation: Vegf-A mRNA transfection before transplantation provides a promising and safe strategy to improve engraftment of islets and other cell-based implants.
- Published
- 2018
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14. (Re)generating Human Beta Cells: Status, Pitfalls, and Perspectives.
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Baeyens L, Lemper M, Staels W, De Groef S, De Leu N, Heremans Y, German MS, and Heimberg H
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- Animals, Homeostasis, Humans, Insulin-Secreting Cells transplantation, Cell Culture Techniques, Insulin-Secreting Cells physiology, Regeneration
- Abstract
Diabetes mellitus results from disturbed glucose homeostasis due to an absolute (type 1) or relative (type 2) deficiency of insulin, a peptide hormone almost exclusively produced by the beta cells of the endocrine pancreas in a tightly regulated manner. Current therapy only delays disease progression through insulin injection and/or oral medications that increase insulin secretion or sensitivity, decrease hepatic glucose production, or promote glucosuria. These drugs have turned diabetes into a chronic disease as they do not solve the underlying beta cell defects or entirely prevent the long-term complications of hyperglycemia. Beta cell replacement through islet transplantation is a more physiological therapeutic alternative but is severely hampered by donor shortage and immune rejection. A curative strategy should combine newer approaches to immunomodulation with beta cell replacement. Success of this approach depends on the development of practical methods for generating beta cells, either in vitro or in situ through beta cell replication or beta cell differentiation. This review provides an overview of human beta cell generation.
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- 2018
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15. Conditional islet hypovascularisation does not preclude beta cell expansion during pregnancy in mice.
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Staels W, Heremans Y, Leuckx G, Van Gassen N, Salinno C, De Groef S, Cools M, Keshet E, Dor Y, Heimberg H, and De Leu N
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- Animals, Cell Proliferation genetics, Cell Proliferation physiology, Cell Size, Female, Islets of Langerhans metabolism, Mice, Pregnancy, Rats, Signal Transduction genetics, Signal Transduction physiology, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor Receptor-1 genetics, Vascular Endothelial Growth Factor Receptor-1 metabolism, Insulin-Secreting Cells metabolism
- Abstract
Aims/hypothesis: Endothelial-endocrine cell interactions and vascular endothelial growth factor (VEGF)-A signalling are deemed essential for maternal islet vascularisation, glucose control and beta cell expansion during mouse pregnancy. The aim of this study was to assess whether pregnancy-associated beta cell expansion was affected under conditions of islet hypovascularisation., Methods: Soluble fms-like tyrosine kinase 1 (sFLT1), a VEGF-A decoy receptor, was conditionally overexpressed in maternal mouse beta cells from 1.5 to 14.5 days post coitum. Islet vascularisation, glycaemic control, beta cell proliferation, individual beta cell size and total beta cell volume were assessed in both pregnant mice and non-pregnant littermates., Results: Conditional overexpression of sFLT1 in beta cells resulted in islet hypovascularisation and glucose intolerance in both pregnant and non-pregnant mice. In contrast to non-pregnant littermates, glucose intolerance in pregnant mice was transient. sFLT1 overexpression did not affect pregnancy-associated changes in beta cell proliferation, individual beta cell size or total beta cell volume., Conclusions/interpretation: Reduced intra-islet VEGF-A signalling results in maternal islet hypovascularisation and impaired glycaemic control but does not preclude beta cell expansion during mouse pregnancy.
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- 2017
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16. A combination of cytokines EGF and CNTF protects the functional beta cell mass in mice with short-term hyperglycaemia.
- Author
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Lemper M, De Groef S, Stangé G, Baeyens L, and Heimberg H
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- Alloxan toxicity, Animals, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Blood Glucose drug effects, Insulin metabolism, Male, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Signal Transduction drug effects, Ciliary Neurotrophic Factor therapeutic use, Epidermal Growth Factor therapeutic use, Hyperglycemia drug therapy, Insulin-Secreting Cells drug effects, Insulin-Secreting Cells metabolism
- Abstract
Aims/hypothesis: When the beta cell mass or function declines beyond a critical point, hyperglycaemia arises. Little is known about the potential pathways involved in beta cell rescue. As two cytokines, epidermal growth factor (EGF) and ciliary neurotrophic factor (CNTF), restored a functional beta cell mass in mice with long-term hyperglycaemia by reprogramming acinar cells that transiently expressed neurogenin 3 (NGN3), the current study assesses the effect of these cytokines on the functional beta cell mass after an acute chemical toxic insult., Methods: Glycaemia and insulin levels, pro-endocrine gene expression and beta cell origin, as well as the role of signal transducer and activator of transcription 3 (STAT3) signalling, were assessed in EGF+CNTF-treated mice following acute hyperglycaemia., Results: The mice were hyperglycaemic 1 day following i.v. injection of the beta cell toxin alloxan, when the two cytokines were applied. One week later, 68.6 ± 4.6% of the mice had responded to the cytokine treatment and increased their insulin(+) cell number to 30% that of normoglycaemic control mice, resulting in restoration of euglycaemia. Although insulin(-) NGN3(+) cells appeared following acute EGF+CNTF treatment, genetic lineage tracing showed that the majority of the insulin(+) cells originated from pre-existing beta cells. Beta cell rescue by EGF+CNTF depends on glycaemia rather than on STAT3-induced NGN3 expression in acinar cells., Conclusions/interpretation: In adult mice, EGF+CNTF allows the rescue of beta cells in distress when treatment is given shortly after the diabetogenic insult. The rescued beta cells restore a functional beta cell mass able to control normal blood glucose levels. These findings may provide new insights into compensatory pathways activated early after beta cell loss.
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- 2016
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17. Sources of beta cells inside the pancreas.
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De Groef S, Staels W, Van Gassen N, Lemper M, Yuchi Y, Sojoodi M, Bussche L, Heremans Y, Leuckx G, De Leu N, Van de Casteele M, Baeyens L, and Heimberg H
- Subjects
- Animals, Cell Differentiation physiology, Humans, Macrophages metabolism, Transcription Factors metabolism, Insulin-Secreting Cells cytology, Insulin-Secreting Cells metabolism, Pancreas cytology
- Abstract
The generation of beta(-like) cells to compensate for their absolute or relative shortage in type 1 and type 2 diabetes is an obvious therapeutic strategy. Patients first received grafts of donor islet cells over 25 years ago, but this procedure has not become routine in clinical practice because of a donor cell shortage and (auto)immune problems. Transplantation of differentiated embryonic and induced pluripotent stem cells may overcome some but not all the current limitations. Reprogramming exocrine cells towards functional beta(-like) cells would offer an alternative abundant and autologous source of beta(-like) cells. This review focuses on work by our research group towards achieving such a source of cells. It summarises a presentation given at the 'Can we make a better beta cell?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Amin Ardestani and Kathrin Maedler, DOI: 10.1007/s00125-016-3892-9 , and by Heiko Lickert and colleagues, DOI: 10.1007/s00125-016-3949-9 ) and a commentary by the Session Chair, Shanta Persaud (DOI: 10.1007/s00125-016-3870-2 ).
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- 2016
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18. Estrogen Receptor α Regulates β-Cell Formation During Pancreas Development and Following Injury.
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Yuchi Y, Cai Y, Legein B, De Groef S, Leuckx G, Coppens V, Van Overmeire E, Staels W, De Leu N, Martens G, Van Ginderachter JA, Heimberg H, and Van de Casteele M
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- Animals, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Cell Nucleus metabolism, Estrogen Receptor alpha metabolism, Insulin-Secreting Cells cytology, Mice, Mice, Knockout, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Pancreas cytology, Cell Proliferation genetics, Estradiol metabolism, Estrogen Receptor alpha genetics, Gene Expression Regulation, Developmental, Insulin-Secreting Cells metabolism, Pancreas embryology, Pancreatic Ducts injuries, RNA, Messenger metabolism
- Abstract
Identifying pathways for β-cell generation is essential for cell therapy in diabetes. We investigated the potential of 17β-estradiol (E2) and estrogen receptor (ER) signaling for stimulating β-cell generation during embryonic development and in the severely injured adult pancreas. E2 concentration, ER activity, and number of ERα transcripts were enhanced in the pancreas injured by partial duct ligation (PDL) along with nuclear localization of ERα in β-cells. PDL-induced proliferation of β-cells depended on aromatase activity. The activation of Neurogenin3 (Ngn3) gene expression and β-cell growth in PDL pancreas were impaired when ERα was turned off chemically or genetically (ERα(-/-)), whereas in situ delivery of E2 promoted β-cell formation. In the embryonic pancreas, β-cell replication, number of Ngn3(+) progenitor cells, and expression of key transcription factors of the endocrine lineage were decreased by ERα inactivation. The current study reveals that E2 and ERα signaling can drive β-cell replication and formation in mouse pancreas., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)
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- 2015
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19. Surgical Injury to the Mouse Pancreas through Ligation of the Pancreatic Duct as a Model for Endocrine and Exocrine Reprogramming and Proliferation.
- Author
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De Groef S, Leuckx G, Van Gassen N, Staels W, Cai Y, Yuchi Y, Coppens V, De Leu N, Heremans Y, Baeyens L, Van de Casteele M, and Heimberg H
- Subjects
- Animals, Cell Differentiation physiology, Cell Proliferation physiology, Humans, Intraoperative Complications pathology, Ligation methods, Male, Mice, Mice, Inbred BALB C, Pancreas cytology, Cellular Reprogramming physiology, Insulin-Secreting Cells cytology, Pancreas injuries, Pancreatic Ducts surgery
- Abstract
Expansion of pancreatic beta cells in vivo or ex vivo, or generation of beta cells by differentiation from an embryonic or adult stem cell, can provide new expandable sources of beta cells to alleviate the donor scarcity in human islet transplantation as therapy for diabetes. Although recent advances have been made towards this aim, mechanisms that regulate beta cell expansion and differentiation from a stem/progenitor cell remain to be characterized. Here, we describe a protocol for an injury model in the adult mouse pancreas that can function as a tool to study mechanisms of tissue remodeling and beta cell proliferation and differentiation. Partial duct ligation (PDL) is an experimentally induced injury of the rodent pancreas involving surgical ligation of the main pancreatic duct resulting in an obstruction of drainage of exocrine products out of the tail region of the pancreas. The inflicted damage induces acinar atrophy, immune cell infiltration and severe tissue remodeling. We have previously reported the activation of Neurogenin (Ngn) 3 expressing endogenous progenitor-like cells and an increase in beta cell proliferation after PDL. Therefore, PDL provides a basis to study signals involved in beta cell dynamics and the properties of an endocrine progenitor in adult pancreas. Since, it still remains largely unclear, which factors and pathways contribute to beta cell neogenesis and proliferation in PDL, a standardized protocol for PDL will allow for comparison across laboratories.
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- 2015
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20. Concise Review: Macrophages: Versatile Gatekeepers During Pancreatic β-Cell Development, Injury, and Regeneration.
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Van Gassen N, Staels W, Van Overmeire E, De Groef S, Sojoodi M, Heremans Y, Leuckx G, Van de Casteele M, Van Ginderachter JA, Heimberg H, and De Leu N
- Subjects
- Animals, Diabetes Mellitus, Type 1 metabolism, Diabetes Mellitus, Type 1 pathology, Diabetes Mellitus, Type 1 therapy, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 2 pathology, Diabetes Mellitus, Type 2 therapy, Humans, Macrophages pathology, Pancreatitis metabolism, Pancreatitis pathology, Pancreatitis therapy, Insulin-Secreting Cells metabolism, Insulin-Secreting Cells pathology, Macrophages metabolism, Regeneration
- Abstract
Unlabelled: Macrophages are classically considered detrimental for pancreatic β-cell survival and function, thereby contributing to β-cell failure in both type 1 (T1D) and 2 (T2D) diabetes mellitus. In addition, adipose tissue macrophages negatively influence peripheral insulin signaling and promote obesity-induced insulin resistance in T2D. In contrast, recent data unexpectedly uncovered that macrophages are not only able to protect β cells during pancreatitis but also to orchestrate β-cell proliferation and regeneration after β-cell injury. Moreover, by altering their activation state, macrophages are able to improve insulin resistance in murine models of T2D. This review will elaborate on current insights in macrophage heterogeneity and on the evolving role of pancreas macrophages during organogenesis, tissue injury, and repair. Additional identification of macrophage subtypes and of their secreted factors might ultimately translate into novel therapeutic strategies for both T1D and T2D., Significance: Diabetes mellitus is a pandemic disease, characterized by severe acute and chronic complications. Macrophages have long been considered prime suspects in the pathogenesis of both type 1 and 2 diabetes mellitus. In this concise review, current insights in macrophage heterogeneity and on the, as yet, underappreciated role of alternatively activated macrophages in insulin sensing and β-cell development/repair are reported. Further identification of macrophage subtypes and of their secreted factors might ultimately translate into novel therapeutic strategies for diabetes mellitus., (©AlphaMed Press.)
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- 2015
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21. Macrophage dynamics are regulated by local macrophage proliferation and monocyte recruitment in injured pancreas.
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Van Gassen N, Van Overmeire E, Leuckx G, Heremans Y, De Groef S, Cai Y, Elkrim Y, Gysemans C, Stijlemans B, Van de Casteele M, De Baetselier P, De Leu N, Heimberg H, and Van Ginderachter JA
- Subjects
- Animals, Antigens, Ly metabolism, Cell Movement immunology, Cell Proliferation, Cellular Microenvironment immunology, Histocompatibility Antigens Class II metabolism, Ligation, Macrophage Activation, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Myeloid Cells classification, Myeloid Cells immunology, Myeloid Cells pathology, Pancreas pathology, Pancreatic Ducts injuries, Receptor, Macrophage Colony-Stimulating Factor metabolism, Regeneration immunology, Macrophages immunology, Macrophages pathology, Monocytes immunology, Monocytes pathology, Pancreas immunology, Pancreas injuries
- Abstract
Pancreas injury by partial duct ligation (PDL) activates a healing response, encompassing β-cell neogenesis and proliferation. Macrophages (MΦs) were recently shown to promote β-cell proliferation after PDL, but they remain poorly characterized. We assessed myeloid cell diversity and the factors driving myeloid cell dynamics following acute pancreas injury by PDL. In naive and sham-operated pancreas, the myeloid cell compartment consisted mainly of two distinct tissue-resident MΦ types, designated MHC-II(lo) and MHC-II(hi) MΦs, the latter being predominant. MHC-II(lo) and MHC-II(hi) pancreas MΦs differed at the molecular level, with MHC-II(lo) MΦs being more M2-activated. After PDL, there was an early surge of Ly6C(hi) monocyte infiltration in the pancreas, followed by a transient MHC-II(lo) MΦ peak and ultimately a restoration of the MHC-II(hi) MΦ-dominated steady-state equilibrium. These intricate MΦ dynamics in PDL pancreas depended on monocyte recruitment by C-C chemokine receptor 2 and macrophage-colony stimulating factor receptor as well as on macrophage-colony stimulating factor receptor-dependent local MΦ proliferation. Functionally, MHC-II(lo) MΦs were more angiogenic. We further demonstrated that, at least in C-C chemokine receptor 2-KO mice, tissue MΦs, rather than Ly6C(hi) monocyte-derived MΦs, contributed to β-cell proliferation. Together, our study fully characterizes the MΦ subsets in the pancreas and clarifies the complex dynamics of MΦs after PDL injury., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2015
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22. Partial duct ligation: β-cell proliferation and beyond.
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Van de Casteele M, Leuckx G, Cai Y, Yuchi Y, Coppens V, De Groef S, Van Gassen N, Baeyens L, Heremans Y, Wright CV, and Heimberg H
- Subjects
- Animals, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Cell Proliferation, Gene Expression Regulation, Ligation, Male, Mice, Models, Animal, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Pancreatic Ducts pathology, Insulin-Secreting Cells cytology, Pancreatic Ducts injuries
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- 2014
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23. IL-6-dependent proliferation of alpha cells in mice with partial pancreatic-duct ligation.
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Cai Y, Yuchi Y, De Groef S, Coppens V, Leuckx G, Baeyens L, Van de Casteele M, and Heimberg H
- Subjects
- Animals, Cell Size, Glucagon-Secreting Cells metabolism, Ligation, Mice, Pancreatic Ducts metabolism, Cell Proliferation physiology, Glucagon-Secreting Cells cytology, Interleukin-6 metabolism, Pancreatic Ducts cytology
- Abstract
Aims/hypothesis: IL-6 was recently shown to control alpha cell expansion. As beta cells expand following partial pancreatic-duct ligation (PDL) in adult mice, we investigated whether PDL also causes alpha cells to expand and whether IL-6 signalling is involved. As alpha cells can reprogramme to beta cells in a number of beta cell (re)generation models, we examined whether this phenomenon also exists in PDL pancreas., Methods: Total alpha cell volume, alpha cell size and total glucagon content were evaluated in equivalent portions of PDL- and sham-operated mouse pancreases. Proliferation of glucagon(+) cells was assessed by expression of the proliferation marker Ki67. Inter-conversions between alpha and beta cells were monitored in transgenic mice with conditional cell-type-specific labelling. The role of IL-6 in regulating alpha cell proliferation was evaluated by in situ delivery of an IL-6-inactivating antibody., Results: In response to PDL surgery, alpha cell volume in the ligated tissue was increased threefold, glucagon content fivefold and alpha cell size by 10%. Activation of alpha cell proliferation in PDL pancreas required IL-6 signalling. A minor fraction of alpha cells derived from beta cells, whereas no evidence for alpha to beta cell conversion was obtained., Conclusions/interpretation: In PDL-injured adult mouse pancreas, new alpha cells are generated mainly by IL-6-dependent self-duplication and seldom by reprogramming of beta cells.
- Published
- 2014
- Full Text
- View/download PDF
24. Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice.
- Author
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Baeyens L, Lemper M, Leuckx G, De Groef S, Bonfanti P, Stangé G, Shemer R, Nord C, Scheel DW, Pan FC, Ahlgren U, Gu G, Stoffers DA, Dor Y, Ferrer J, Gradwohl G, Wright CV, Van de Casteele M, German MS, Bouwens L, and Heimberg H
- Subjects
- Acinar Cells drug effects, Acinar Cells pathology, Animals, Cell Differentiation drug effects, Cell Proliferation drug effects, Ciliary Neurotrophic Factor genetics, Diabetes Mellitus genetics, Epidermal Growth Factor genetics, Hyperglycemia drug therapy, Insulin-Secreting Cells pathology, Mice, Mice, Inbred NOD genetics, Signal Transduction, Ciliary Neurotrophic Factor administration & dosage, Diabetes Mellitus drug therapy, Epidermal Growth Factor administration & dosage, Insulin-Secreting Cells drug effects
- Abstract
Reprogramming of pancreatic exocrine cells into cells resembling beta cells may provide a strategy for treating diabetes. Here we show that transient administration of epidermal growth factor and ciliary neurotrophic factor to adult mice with chronic hyperglycemia efficiently stimulates the conversion of terminally differentiated acinar cells to beta-like cells. Newly generated beta-like cells are epigenetically reprogrammed, functional and glucose responsive, and they reinstate normal glycemic control for up to 248 d. The regenerative process depends on Stat3 signaling and requires a threshold number of Neurogenin 3 (Ngn3)-expressing acinar cells. In contrast to previous work demonstrating in vivo conversion of acinar cells to beta-like cells by viral delivery of exogenous transcription factors, our approach achieves acinar-to-beta-cell reprogramming through transient cytokine exposure rather than genetic modification.
- Published
- 2014
- Full Text
- View/download PDF
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