title: 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.
authors.affiliation: Diabetes and Metabolism Research Institute and Beckman Research Institute, City of Hope, Duarte, CA 91010;
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Diabetes and Metabolism Research Institute and Beckman Research Institute, City of Hope, Duarte, CA 91010; Department of Clinical Laboratory, People's Hospital Affiliated to Fujian Traditional Chinese Medicine University, Fuzhou 350004, China;
authors.forename: Qing
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Eugene and Ruth Roberts Summer Student Academy, City of Hope, Duarte, CA 91010.
authors.forename: Tong
authors.initials: T
authors.lastname: Qi
authors.affiliation: Eugene and Ruth Roberts Summer Student Academy, City of Hope, Duarte, CA 91010.
authors.forename: Tiankun
authors.initials: T
authors.lastname: Wang
authors.affiliation: Diabetes and Metabolism Research Institute and Beckman Research Institute, City of Hope, Duarte, CA 91010;
authors.forename: Ching-Cheng
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Diabetes and Metabolism Research Institute and Beckman Research Institute, City of Hope, Duarte, CA 91010; dzeng@coh.org ariggs@coh.org.
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Riggs
authors.affiliation: Diabetes and Metabolism Research Institute and Beckman Research Institute, City of Hope, Duarte, CA 91010; dzeng@coh.org ariggs@coh.org.
authors.forename: Defu
authors.initials: D
authors.lastname: Zeng
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D003470:Culture Media / Q000737:chemistry*; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000494:pharmacology*; D005755:Gastrins / Q000008:administration & dosage / Q000494:pharmacology*; D006943:Hyperglycemia / Q000150:complications* / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000473:pathology*; D007700:Kinetics; D008810:Mice, Inbred C57BL; D010183:Pancreatic Ducts / Q000473:pathology*; D055758:SOX9 Transcription Factor / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D003470:Culture Media; D005755:Gastrins; D055758:SOX9 Transcription Factor; D004815:Epidermal Growth Factor
keywords: Sox9+ ductal cells; epidermal growth factor; gastrin; hyperglycemia; β-cell differentiation