Reference : Pancreatic Beta Cell Regeneration in Zebrafish : Investigation of the Ductal Contribu...
Dissertations and theses : Doctoral thesis
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/2268/229507
Pancreatic Beta Cell Regeneration in Zebrafish : Investigation of the Ductal Contribution and Involved Molecular Mechanisms
English
Bergemann, David mailto [Université de Liège - ULiège > > > Doct. sc. (bioch., biol. mol.&cell., bioinf.&mod.-Bologne)]
Dec-2018
Université de Liège, ​Liège, ​​Belgique
Docteur en Sciences
197
Manfroid, Isabelle mailto
Sadzot, Catherine mailto
Muller, Marc mailto
Dequiedt, Franck mailto
Scharfmann, Raphaël mailto
Heimberg, Harry mailto
Vanhollebeke, Benoît mailto
[en] Pancreas ; Zebrafish ; Beta cell ; Diabetes ; Regeneration ; pancreatic ducts
[en] The pancreas, along with its major role in digestion, holds one of the most important cell type involved in glucose homeostasis : the insulin-producing β cell.
Diabetes mellitus is characterized by a disturbed blood glucose balance resulting from a lack or an inadequate secretion/action of insulin. A hallmark of diabetes is the loss of β cells either by an autoimmune destruction (T1D) or by an ongoing exhaustion and subsequent cell death associated with the inability to fit metabolic demands (T2D).
As this disease has become a major burden in our modern society, efforts are needed to provide effective therapeutic strategies. While current strategies rely on exogenous insulin supply and glycemic control through medication, restoring a functional β cell pool represents the most promising solution to tackle the disease at its root. To this regard, regeneration studies have provided evidence that β cells can be produced by stimulating their replication or by (trans)differentiation of different cellular sources.
In this work, we investigated the possibility that the pancreatic ductal compartment can be a source of regenerated β cells. In order to study regeneration and unravel underlying mechanisms, we conducted our work in the regeneration prone zebrafish model which was previously shown to regenerate its β cells in a very efficient manner.
By using a combination of transgenic tools and deep RNA-sequencing, we were able to show that adult pancreatic duct cells display a progenitor-like behavior and that they constitute a source of regenerated β cells.
We then used comparative transcriptomics in order to get an insight into the molecular mechanisms (gene regulation) occurring in the ductal cells during regeneration. This provided us with candidate signaling pathways and genes possibly involved in regeneration. To determine their importance in this process, we initiated functional studies by targeting pathways with pharmacological inhibitors/activators. Among the candidates, the Ca2+/calcineurin signaling axis seemed most promising and will be further investigated for its implication in regeneration.
In parallel, we also underlined an important pro-endocrine role for the transcription factor ascl1b in β cell regeneration from the ducts.
Lastly, this work prompted us to further improve the nitroreductase-mediated ablation system used in regeneration studies. Thus we characterized Nifurpirinol as a more potent substrate than the gold-standard prodrug Metronidazole which displayed suboptimal and variable cell ablation efficiencies.
Altogether, our work strengthens the hypothesis that adult pancreatic ducts contain progenitors able to differentiate into β cells and provides new research leads regarding targetable signaling pathways and genes for the stimulation of β cell regeneration. Understanding the fundamentals of β cell regeneration taking place in zebrafish might thus pave the way towards stimulating these mechanisms in diabetic patients.
Giga-Molecular Biology of Diseases, Laboratory of Zebrafish Development and Disease Models
Fonds pour la formation à la Recherche dans l'Industrie et dans l'Agriculture (Communauté française de Belgique) - FRIA ; Fonds Léon Fredericq ; Fonds de la Recherche Scientifique (Communauté française de Belgique) - F.R.S.-FNRS
Pancreatic Regeneration in Zebrafish
Researchers
http://hdl.handle.net/2268/229507

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