Gastrin induces ductal cell dedifferentiation and β-cell neogenesis after 90% pancreatectomy

Abstract

Induction of b-cell mass regeneration is a potentially curative treatment for diabetes. We have recently found that long-term gastrin treatment results in improved metabolic control and b-cell mass expansion in 95% pancreatectomised (Px) rats. In this study, we investigated the underlying mechanisms of gastrin-induced b-cell mass expansion after Px. After 90%-Px, rats were treated with gastrin (PxCG) or vehicle (PxCV), pancreatic remnants were harvested on days 1, 3, 5, 7, and 14 and used for gene expression, protein immunolocalisation and morphometric analyses. Gastrin-and vehicle-treated Px rats showed similar blood glucose levels throughout the study. Initially, after Px, focal areas of regeneration, showing mesenchymal cells surrounding ductal structures that expressed the cholecystokinin B receptor, were identified. These focal areas of regeneration were similar in size and cell composition in the PxCG and PxCV groups. However, in the PxCG group, the ductal structures showed lower levels of keratin 20 and b-catenin (indicative of duct dedifferentiation) and higher levels of expression of neurogenin 3 and NKX6-1 (indicative of endocrine progenitor phenotype), as compared with PxCV rats. In PxCG rats, b-cell mass and the number of scattered b-cells were significantly increased compared with PxCV rats, whereas b-cell replication and apoptosis were similar in the two groups. These results indicate that gastrin treatment-enhanced dedifferentiation and reprogramming of regenerative ductal cells in Px rats, increased b-cell neogenesis and fostered b-cell mass expansion.

The association between Helicobacter pylori seropositivity and risk of new-onset diabetes: a prospective cohort study

“…Several studies have reported that H. pylori seropositivity was associated with different hormones [2,[8][9][10], most of which were involved in glucose metabolism directly or indirectly [11][12][13][14][15][16][17]. To our knowledge, at least three hormones supported our results, including gastrin, leptin and ghrelin.…”

β-cell replacement sources for type 1 diabetes: a focus on pancreatic ductal cells

“…Because of potential implications of gastrin in β-cell mass regeneration in rodents [Suarez-Pinzon et al 2008;Suissa et al 2013], a recent study evaluated the role of gastrin in promoting β-cell neogenesis from ductal cells in 90% Px rats [Tellez and Montanya, 2014]. In the gastrin-treated mice, strong proliferation activity was Xu et al [2006] In vivo Treatment with exendin-4 facilitated β-cell neogenesis in pancreatic ducts Tokui et al [2006] In vivo Betacellulin promoted ductal differentiation towards insulin-expressing cells Inada et al [2008] In vivo β-cell mass replenishment occurred from ductal cells 2 weeks post PDL Bonner-Weir et al [2008] In vivo Partial pancreatic tissue regeneration occurred from ductal cells Xu et al [2008] In vivo Re-expression of NGN3 in ductal lining cells occurred 1 week after PDL Criscimanna et al [2011] In vivo Proliferative ducts expressed acinar and endocrine markers 3/4 weeks post-DT injection Wang et al [2012] In vivo Administration of gastrin and EGF increased β-cell neogenesis Pfeifer et al [2013] In vivo Requirement of EMT for duct-lining cells differentiation into endocrine cells In vivo Continuous activation of NGN3 + cells along the lining duct occurred after ARX inhibition Téllez et al [2014] In vivo Appearance of β-cell clusters from ductal epithelium occurred 3 days post 90% Px Lemaire et al [2015] In vivo Bicaudal C1 expressed in duct lining cells was essential for progenitor differentiation Yamaguchi et al [2015] In vivo Pancreatic ductal glands contained niches of progenitor cells Carpino et al [2015] In vivo Pancreatic ductal glands as container of niches for pancreatic precursors Napolitano et al [2015] In vivo Continuous activation of NGN3 + cells along the lining duct occurred after PAX4 overexpression El-Gohary et al [2016] In vivo Duct-to-β-cell conversion occurred after partial Px in mice overexpressing TGF-β receptor Zhang et al [2016] In vivo Conversion of SOX9 + cells into insulin-producing cells occurred after administration of gastrin and EGF Seaberg et al [2004] In vitro Progenitor colonies arose from islet and ducts cultured with EGF and FGF2 Rovira et al [2010] In vitro Centroacinar/terminal ductal cells with progenitor-like phenotype ARX, aristaless related homeobox; DT, diphtheria toxin; EGF, epidermal growth factor; EMT, epithelial-mesenchymal transition; PDL, pancreatic duct ligation; Px, pancreatectomy; TGF, transforming growth factor.…”

β-Cell dedifferentiation, reduced duct cell plasticity, and impaired β-cell mass regeneration in middle-aged rats

“…Ninety percent Px was performed as described previously (50). Briefly, animals were anesthetized with 5% isoflurane (Forane; Abbott) and maintained anesthetized with an isoflurane (1.5%) air mixture.…”

“…Thus, duct cell mass was determined using the traditional point-counting method on keratin 20-labeled sections (Table 1) (50). A nomogram relating number of points counted to volume density and expected relative standard error in percentage of mean (Ͻ10%) was used to determine the number of intercepts needed for a representative sampling (32).…”

“…In young rodents, gastrin overexpression and pharmacological treatment stimulate duct cell plasticity, leading to ␤-cell neogenesis (36,46,53,57), and in Px rats gastrin treatment stimulates duct cell plasticity, ␤-cell neogenesis, and ␤-cell replication, resulting in increased ␤-cell mass and improved metabolic control (49,50). In this study we have used these two different experimental conditions, the 90%-Px model and gastrin treatment, to investigate the ␤-cell regeneration potential of middle-aged rats.…”