Growth factors and medium hyperglycemia induce Sox9⁺ductal cell differentiation into β cells in mice with reversal of diabetes

Abstract

We previously reported that long-term administration of a low dose of gastrin and epidermal growth factor (GE) augments β-cell neogenesis in late-stage diabetic autoimmune mice after eliminating insulitis by induction of mixed chimerism. However, the source of β-cell neogenesis is still unknown. SRY (sex-determining region Y)-box 9 + (Sox9 + ) ductal cells in the adult pancreas are clonogenic and can give rise to insulin-producing β cells in an in vitro culture. Whether Sox9 + ductal cells in the adult pancreas can give rise to β cells in vivo remains controversial. Here, using lineage-tracing with genetic labeling of Insulin-or Sox9-expressing cells, we show that hyperglycemia (>300 mg/dL) is required for inducing Sox9 + ductal cell differentiation into insulin-producing β cells, and medium hyperglycemia (300-450 mg/dL) in combination with long-term administration of low-dose GE synergistically augments differentiation and is associated with normalization of blood glucose in nonautoimmune diabetic C57BL/6 mice. Short-term administration of high-dose GE cannot augment differentiation, although it can augment preexisting β-cell replication. These results indicate that medium hyperglycemia combined with long-term administration of low-dose GE represents one way to induce Sox9 + ductal cell differentiation into β cells in adult mice.

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.…”

Effect of Platelet Rich Plasma (PRP) Injection on the Endocrine Pancreas of the Experimentally Induced Diabetes in Male Albino Rats: A Histological and Immunohistochemical Study

“…Growth factors (GFs) are natural biological mediators that control growth, differentiation, and have role in the process of tissue repair and regeneration [9]. Recently, long-term administration of a low dose of epidermal growth factor (EGF) induces β-cell neo-genesis in diabetic mice and induced ductal cell differentiation into β-cells [10]. Platelets convey many growth factors (GFs) [11].…”

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

“…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.…”