References of "Manfroid, Isabelle"
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See detailIdentification of Signaling Pathways regulating beta cell regeneration
Massoz, Laura ULiege; Manfroid, Isabelle ULiege

Conference (2019, May 17)

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See detailCharacterization of regenerated beta cells in zebrafish
Manfroid, Isabelle ULiege

Speech/Talk (2018)

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See detailPancreatic delta cells could be a new source of beta cells in adult zebrafish
Carril Pardo, Claudio Andrès ULiege; Bergemann, David ULiege; Massoz, Laura ULiege et al

Poster (2018, June 04)

Diabetes occurs under insulin resistance/deficiency and when insulin-producing pancreatic beta-cell mass is dramatically reduced. Besides therapeutic strategies to preserve beta-cell mass and function and ... [more ▼]

Diabetes occurs under insulin resistance/deficiency and when insulin-producing pancreatic beta-cell mass is dramatically reduced. Besides therapeutic strategies to preserve beta-cell mass and function and improve insulin treatments, beta-cell replacement constitutes a promising alternative to replenish the pancreas with functional beta-cells. Several observations of pancreatic cell plasticity has led to the hope that triggering beta-cell regeneration within the pancreas could be harnessed in future therapies. Notably, endocrine alpha- and delta-cells have been shown in mouse to convert or transdifferentiate into beta-cell after massive destruction in adult and juvenile, respectively [1] [2]. Due to its potent regenerative capabilities, zebrafish, unlike mammals, is a model of choice to dissect the cellular and molecular mechanisms underlying beta-cell regeneration. Using a chemogenetic model to induce selective destruction of beta-cells, we recently showed that adult zebrafish duct cells display characteristics of embryonic pancreatic progenitors and that they can give rise to beta-cells in physiological and induced diabetic condition [3]. In this study we pretend to search new sources of beta cell regeneration and understand the underlying molecular and cellular basis in zebrafish. Indeed, recent observations in our laboratory reveal the appearance of bi-hormonal Somatostatin/Insulin (Sst/ Ins) cells during beta-cell regeneration in adult zebrafish. This suggests 1) other cellular origins of the regenerated beta-cells, ie the endocrine delta-cells that express somatostatin (Sst) or 2) that regenerated beta-cells display different features as compared to the original ones. To assess both possibilities, we analyzed these bi-hormonal cells at different time points during regeneration and at different ages. Here, we show the appearance of bi-hormonal cells (Sst/ Ins) after beta-cell ablation in embryos and larvae in the regeneration stage, similar to those observed in adult fish. Transcriptomic analyses from adult zebrafish further show that at least some regenerated beta cells have poly-hormonal characteristics corresponding to other pancreatic and non-pancreatic endocrine cells. We are currently investigating whether these features affect the function of the regenerated beta-cells and if delta-cells give rise to new betacells in zebrafish by lineage tracing studies. [less ▲]

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See detailIdentification of Pax6-dependent regulatory networks during endocrine pancreatic cells and enteroendocrine cells differentiation in zebrafish
Lavergne, Arnaud ULiege; Tarifeno, Estefania; Pirson, Justine et al

Poster (2018, April 09)

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See detailMiR-337-3p controls hepatobiliary gene expression and transcriptional dynamics during hepatic cell differentiation.
Demarez, Celine; Gerard, Claude; Cordi, Sabine et al

in Hepatology (2018)

Transcriptional networks control the differentiation of the hepatocyte and cholangiocyte lineages from embryonic liver progenitor cells, and their subsequent maturation to the adult phenotype. However ... [more ▼]

Transcriptional networks control the differentiation of the hepatocyte and cholangiocyte lineages from embryonic liver progenitor cells, and their subsequent maturation to the adult phenotype. However, how accurate levels of hepatocyte and cholangiocyte gene expression are determined during differentiation remains poorly understood. Here we identify miR-337-3p as a novel regulator of liver development. MiR-337-3p stimulates expression of cholangiocyte genes and represses hepatocyte genes in undifferentiated progenitor cells in vitro and in embryonic mouse livers. Beyond the stage of lineage segregation, miR-337-3p controls the transcriptional network dynamics of developing hepatocytes, and balances both cholangiocyte populations that constitute the ductal plate. MiR-337-3p requires Notch and Transforming Growth Factor-beta signaling, and exerts a biphasic control on the hepatocyte transcription factor Hepatocyte Nuclear Factor (HNF) 4alpha, by modulating its activation and repression. With help of an experimentally validated mathematical model we show that this biphasic control results from an incoherent feedforward loop between miR-337-3p and HNF4alpha. CONCLUSION: Our results identify miR-337-3p as a novel regulator of liver development, and highlight how tight quantitative control of hepatic cell differentiation is exerted via specific gene regulatory network motifs. This article is protected by copyright. All rights reserved. [less ▲]

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See detailNifurpirinol : a more potent and reliable substrate compared to metronidazole for nitroreductase-mediated cell ablations.
Bergemann, David ULiege; Massoz, Laura ULiege; Bourdouxhe, Jordane ULiege et al

in Wound Repair and Regeneration (2018)

The zebrafish is a popular animal model with well-known regenerative capabilities. To study regeneration in this fish, the nitroreductase/metronidazole-mediated system is widely used for targeted ablation ... [more ▼]

The zebrafish is a popular animal model with well-known regenerative capabilities. To study regeneration in this fish, the nitroreductase/metronidazole-mediated system is widely used for targeted ablation of various cell types. Nevertheless, we highlight here some variability in ablation efficiencies with the metronidazole prodrug that led us to search for a more efficient and reliable compound. Herein, we present nifurpirinol, another nitroaromatic antibiotic, as a more potent prodrug compared to metronidazole to trigger cell-ablation in nitroreductase expressing transgenic models. We show that nifurpirinol induces robust and reliable ablations at concentrations 2000 fold lower than metronidazole and three times below its own toxic concentration. We confirmed the efficiency of nifurpirinol in triggering massive ablation of three different cell types: the pancreatic beta cells, osteoblasts and dopaminergic neurons. Our results identify nifurpirinol as a very potent prodrug for the nitroreductase-mediated ablation system and suggest that its use could be extended to many other cell types, especially if difficult to ablate, or when combined pharmacological treatments are desired. This article is protected by copyright. All rights reserved. [less ▲]

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See detailIdentification of Signaling Pathways Regulating Beta Cell Regeneration in Zebrafish
Massoz, Laura; Bergemann, David ULiege; Lavergne, Arnaud ULiege et al

Poster (2017, September 15)

Diabetes is becoming a leading health issue worldwide. It occurs under insulin resistance/deficiency and when insulin-producing pancreatic beta-cell mass is dramatically reduced. Besides therapeutic ... [more ▼]

Diabetes is becoming a leading health issue worldwide. It occurs under insulin resistance/deficiency and when insulin-producing pancreatic beta-cell mass is dramatically reduced. Besides therapeutic strategies to preserve beta-cell mass and function and improve insulin treatments, beta-cell replacement constitutes a promising alternative to replenish the pancreas with functional beta-cells. Beta-cell neogenesis can be achieved from different pancreatic cell types leading to the hope that triggering regeneration could be harnessed in future therapies. Still, mammals show limited regenerative capabilities, making difficult the study of these mechanisms. In contrast, zebrafish is extensively used for regeneration studies notably of beta-cells. We recently showed that the adult zebrafish ducts display characteristics of embryonic pancreatic progenitors that give rise to beta-cells in physiological and induced diabetic condition*. To better understand the molecular mechanisms underlying this potential, genes and signaling pathways regulated in the zebrafish pancreatic ducts after beta-cell ablation have been identified by transcriptomic profiling. For functional studies, we have developed an assay using 7-20 days old larvae to investigate the role of selected candidate pathways in beta-cell regeneration with pharmacological inhibitors/activators and by transgenic overexpression of candidate signaling factors. These results should provide new hints to help improve regenerative competences in mammals. [less ▲]

Detailed reference viewed: 66 (18 ULiège)
See detailToward discovery of novel key genes for pancreatic beta cell regeneration in zebrafish
Carril Pardo, Claudio Andrès ULiege; Bergemann, David ULiege; Massoz, Laura ULiege et al

Poster (2017, September 14)

Diabetes is becoming a leading health issue worldwide. It occurs under insulin resistance/deficiency and when insulin-producing pancreatic beta-cell mass is dramatically reduced. Besides therapeutic ... [more ▼]

Diabetes is becoming a leading health issue worldwide. It occurs under insulin resistance/deficiency and when insulin-producing pancreatic beta-cell mass is dramatically reduced. Besides therapeutic strategies to preserve beta-cell mass and function and improve insulin treatments, beta-cell replacement constitutes a promising alternative to replenish the pancreas with functional beta-cells. Several observations of pancreatic cell plasticity has led to the hope that triggering beta-cell regeneration within the pancreas could be harnessed in future therapies. Still, mammals show limited regenerative capabilities, making difficult the study of these mechanisms. In contrast, zebrafish is extensively used for regeneration studies notably of beta-cells. We recently showed that the adult zebrafish ducts display characteristics of embryonic pancreatic progenitors that can give rise to beta-cells in physiological and induced diabetic condition*, and we determined the transcriptomic profile of zebrafish pancreatic ducts during beta-cell regeneration. To identify new genes crucial for beta-cell regeneration we plan to investigate the role of about 10 selected candidate genes by analyzing invalidating mutations created by CRISPR/Cas9. Their effect on beta-cell regeneration will be studied in 7-20 old larvae which we have established as experimental platform for functional studies. This project should help decipher the molecular mechanism of beta-cell regeneration. [less ▲]

Detailed reference viewed: 105 (13 ULiège)
See detailIdentification of Pax6-dependent regulatory networks during endocrine pancreatic cells and enteroendocrine cells differentiation in zebrafish
Lavergne, Arnaud ULiege; Tarifeno, Estefania; Pirson, Justine et al

Poster (2017, September 14)

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See detailBeta Cell Regeneration in Zebrafish : Investigating the Ductal Contribution
Bergemann, David ULiege; Massoz, Laura; Bourdouxhe, Jordane ULiege et al

Poster (2017, July)

Diabetes is characterized by the loss of insulin producing beta cells. Although different therapeutic strategies do exist, they lack precise and dynamic control of glycemia as carried out by endogenous ... [more ▼]

Diabetes is characterized by the loss of insulin producing beta cells. Although different therapeutic strategies do exist, they lack precise and dynamic control of glycemia as carried out by endogenous beta cells. One promising alternative is to replenish the pancreas with bona fide functional beta cells by triggering regeneration mechanisms. Previous studies have shown beta cell neogenesis originating from different pancreatic cell types (alpha, delta, acinar and ductal cells), depending on the used model. The ductal origin is supported by the fact that the embryonic duct epithelium gives rise to the endocrine lineage, and that in healthy and diabetic human adults, insulin positive cells could be found next to or in pancreatic ducts. Despite these observations, mammals show very limited regenerative capabilities, making it difficult to investigate those mechanisms. In contrast, zebrafish are extensively used for regeneration studies. The ability of adult zebrafish to regenerate its beta cells and restore normoglycemia after massive beta cell ablation has already been shown. We, and other groups, have previously shown that adult pancreatic duct cells act as progenitors, giving rise to beta cells in physiological and induced diabetic condition in vivo. To get insight into this process, we conducted comparative RNA-seq experiments on pancreatic duct cells from adult zebrafish. By this means, we identified regulated gene expression that can be linked to specific processes/pathways such as cell cycling and Notch. In order to confirm the involvement of identified candidate genes/pathways, we are setting up a screening method using chemical activators and inhibitors in old larvae, by looking at their ability to modify proliferation/differentiation of duct cells after beta cell ablation. In addition, we are also investigating the effect of mutations, generated by the CRISPR/Cas9 system within candidate genes, on the regeneration capabilities. Together, these strategies should provide new clues about regenerative processes triggered in duct cells that might be applied to overcome the poor regenerative capabilities of mammals. [less ▲]

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Peer Reviewed
See detailTranscriptome analysis of pancreatic cells across distant species highlights novel important regulator genes
Tarifeño-Saldivia, Estefania; Lavergne, Arnaud ULiege; Bernard, Alice ULiege et al

Conference (2017, March 21)

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See detailPotential use of estetrol in sensorineural hearing loss protection
DELHEZ, Amandine ULiege; Manfroid, Isabelle ULiege; LEFEBVRE, Philippe ULiege et al

in B-ENT (2017)

Introduction and Aims: Estrogens have a positive impact on the auditory function. Indeed, estradiol (E2) treatment in animals protects against acoustic trauma and aminoglycoside toxicity and its depletion ... [more ▼]

Introduction and Aims: Estrogens have a positive impact on the auditory function. Indeed, estradiol (E2) treatment in animals protects against acoustic trauma and aminoglycoside toxicity and its depletion can contribute to age-related hearing loss. However, estradiol is not suitable in clinical practice, given the increased risk of cancer and thromboembolic events. There is a need to find new treatments that present a higher benefit/risk ratio. In this work, we studied a new natural estrogen derivative, estetrol (E4), that was shown to act as a Selective Estrogen Receptor Modulator (SERM). Estetrol is thus able to display estrogen-like as well as antiestrogen activity depending on the target tissue. Interestingly, E4 allows the prevention of menopause symptoms such as osteoporosis or hot flushes through an agonistic action, whereas it exerts anti-estrogenic effects on the mammary gland. These preclinical data suggest that E4 presents a safer profile than E2. Material and Methods: To investigate whether this molecule presents otoprotective actions, we exposed P2 cultured organs of Corti to gentamicin, with or without estetrol (E4). After 48 hours of culture, hair cell survival was evaluated following anti-myosin VII Immunohistochemistry. We next moved on to in vivo studies using young zebrafish larvae (5dpf), since they constitute a highly effective model to determine the potential ototoxicity of drugs and to screen for candidates of hair cell protective agents. We monitored the survival of hair cells within neuromasts following chronic or acute exposure to gentamicin. Results: In cochlear culture, gentamicin-induced hair cell loss was significantly reduced by E4. Interestingly, the toxicity of aminoglycoside was also reduced in vivo upon treatment of zebrafish larvae with E4. Conclusion: The survival rate of hair cells was increased in the presence of estetrol both in vitro and in vivo indicating that estetrol constitutes an interesting protective drug against hearing loss. [less ▲]

Detailed reference viewed: 87 (28 ULiège)
See detailZebrafish: a small fish to tackle alternative routes toward anti-diabetic treatments
Manfroid, Isabelle ULiege

Scientific conference (2016, December 09)

Detailed reference viewed: 16 (1 ULiège)
See detailPancreatic cell differentiation, plasticity and beta cell regeneration
Manfroid, Isabelle ULiege

Scientific conference (2016, December 09)

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Peer Reviewed
See detailBeta cell regeneration from pancreatic ducts in adult zebrafish
Manfroid, Isabelle ULiege

Poster (2016, September 18)

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See detailPancreatic Beta Cell Regeneration: Duct Cells Act as Progenitors in Adult Zebrafish
Bergemann, David ULiege; Ghaye, Aurélie; Tarifeño Saldivia, Estefania ULiege et al

Poster (2016, March 18)

Diabetes is characterized by the loss of insulin producing beta cells. Although different therapeutic strategies do exist, they lack precise and dynamic control of glycemia as carried out by endogenous ... [more ▼]

Diabetes is characterized by the loss of insulin producing beta cells. Although different therapeutic strategies do exist, they lack precise and dynamic control of glycemia as carried out by endogenous beta cells. One promising alternative is to replenish the pancreas with bona fide functional beta cells by triggering regeneration mechanisms. Previous studies have shown beta cell neogenesis but still remain controversial about their origin as they used different models. However, among the different hypotheses, it is tempting to assume that pancreatic ducts contain progenitor/precursor cells in adults. The latter is supported by the fact that the embryonic duct epithelium gives rise to the endocrine lineage, and that in healthy and diabetic human adults, insulin positive cells could be found next to or in pancreatic ducts. Despite these observations, mammals show very limited regenerative capabilities, making it difficult to investigate those mechanisms. In contrast, zebrafish are extensively used for regeneration studies. The ability of adult zebrafish to regenerate its beta cells and restore normoglycemia after massive beta cell ablation has already been shown. Our work focuses on the understanding of the underlying mechanisms leading to this retained potential. Here we show that adult pancreatic duct cells act as progenitors, giving rise to beta cells, in physiological and induced diabetic condition in vivo. To get insight into this process, we conducted RNA-seq experiments on zebrafish pancreatic duct cells. By this mean we could identify new ductal markers and noticed that adult duct cells also show strong expression of embryonic pancreatic progenitor markers. In our ongoing comparative analyses we are deciphering the key genes and pathways needed to set in motion the regenerative machinery. The differences between zebrafish and mammal duct cells that will thereby be underlined might then be transposed to mammalian model s to restore regenerative processes. [less ▲]

Detailed reference viewed: 280 (18 ULiège)