Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice

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 reinstate normal glycemic control for up to 248 days. 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

Diabetes Enhances the Proliferation of Adult Pancreatic Multipotent Progenitor Cells and Biases Their Differentiation to More β-Cell Production

“…The neogenesis was carried out by precursor-like cells that either resided in the ductal epithelium or were spontaneously produced by trans differentiation or dedifferentiation of acinar or ductal cells (39,42,43). In another study, cytokine treatment of overtly diabetic mice induced trans differentiation of acinar cells to b-cell-like cells (44). Our findings suggest that preexisting progenitorlike cells can contribute to b-cell compensation elicited by naturally occurring b-cell stress such as that observed in NOD/NOD.Scid mice, as well as in human diabetic samples.…”

Activation of GLP-1 and gastrin signalling induces in vivo reprogramming of pancreatic exocrine cells into beta cells in mice

“…Here, we demonstrate direct in vivo evidence that gastrin administration alone initiates beta cell neogenesis within exocrine cells and that the concurrent activation of GLP-1 signalling synergistically enhances this effect, although the reprogramming efficiency in our model was lower than that of other reported strategies [1,13]. hypoglycaemia, and basic research has uncovered several mechanisms of their diabetes-protective effects on beta cells, such as the stimulation of insulin secretion, increase in beta cell replication and inhibition of beta cell apoptosis [40].…”

“…To address this question, we applied genetic strategies based on a Cre/loxP-based lineage tracing system and generated a mouse model overexpressing GLP-1 receptor (GLP1R). Whereas no newly generated beta cells were detected by the activation of GLP-1 signalling alone, GLP-1 was able to facilitate beta cell neogenesis initiated by gastrin, although the reprogramming efficiency in our model was not as high as that of other mouse models [1,13]. It is noted that activation of GLP-1 signalling did not induce pancreatitis and pancreatic dysplasia, suggesting that these safety concerns, which have been reported in previous clinical cases and in vivo studies of incretin-based therapies [14][15][16], were abated in our models.…”

“…Therefore, there are a number of possibilities for the origin of newly generated insulin-producing cells; namely, SOX9-expressing progenitors, differentiated duct cells or acinar cells. Several groups have demonstrated that acinar cells can be reprogrammed into beta cells under various conditions [1,13,47]. To clarify the origin of the newly generated insulin-producing cells, further studies should be performed using other Cre-expressing lines that induce Cre-mediated recombination specifically in acinar cells, such as Elastase1-CreER [48] and Ptf1a-CreER mice [47].…”

La thérapie cellulaire du diabète

“…Actifs depuis longtemps dans les investigations visant à stimuler la conversion acinaire-β de manière pharmacologique, l'équipe avait montré l'utilité de facteurs de croissance (epidermal growth factor [EGF]) ou d'hormones (gastrine) dans la régénération des cellules β [47]. L'extension de ces recherches a permis d'identifier deux facteurs, l'EGF et le ciliary neurotrophic factor (CNTF) qui permettent d'induire une transdifférencia-tion acinaire-vers-β massive chez la plupart (65 %) des souris traitées [48]. À l'instar du modèle adénoviral que nous avons rapporté, le cocktail EGF/CNTF a permis la normalisation des glycémies des souris diabétiques (diabète induit par alloxan) seulement cinq jours après traitement par pompes osmotiques.…”