Pancreatic β-cell neogenesis by direct conversion from mature α-cells.
Because type 1 and type 2 diabetes are characterized by loss of β-cells, β-cell regeneration has garnered great interest as an approach to diabetes therapy. Here, we developed a new model of β-cell regeneration, combining pancreatic duct ligation (PDL) with elimination of pre-existing β-cells with alloxan. In this model, in which virtually all β-cells observed are neogenic, large numbers of β-cells were generated within 2 weeks. Strikingly, the neogenic β-cells arose primarily from α-cells. α-cell proliferation was prominent following PDL plus alloxan, providing a large pool of precursors, but we found that β-cells could form from α-cells by direct conversion with or without intervening cell division. Thus, classical asymmetric division was not a required feature of the process of α- to β-cell conversion. Intermediate cells coexpressing α-cell- and β-cell-specific markers appeared within the first week following PDL plus alloxan, declining gradually in number by 2 weeks as β-cells with a mature phenotype, as defined by lack of glucagon and expression of MafA, became predominant. In summary, these data revealed a novel function of α-cells as β-cell progenitors. The high efficiency and rapidity of this process make it attractive for performing the studies required to gain the mechanistic understanding of the process of α- to β-cell conversion that will be required for eventual clinical translation as a therapy for diabetes.
Chung
Cheng-Ho
CH
Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, California, USA.
Hao
Ergeng
E
Piran
Ron
R
Keinan
Ehud
E
Levine
Fred
F
D000367:Age Factors; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D054338:Cell Transdifferentiation; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D005934:Glucagon / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D037181:Lectins, C-Type / Q000378:metabolism; D008026:Ligation; D051258:MafB Transcription Factor / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D015513:Oncogene Proteins / Q000378:metabolism; D010183:Pancreatic Ducts / Q000601:surgery; D010641:Phenotype; D012038:Regeneration; D013997:Time Factors
D015415:Biomarkers; D007328:Insulin; C094696:Klrg1 protein, rat; D037181:Lectins, C-Type; D051258:MafB Transcription Factor; C490405:Mafb protein, rat; D008562:Membrane Glycoproteins; D015513:Oncogene Proteins; D005934:Glucagon