Pancreatic β-Cell Neogenesis by Direct Conversion from Mature α-Cells

被引:148
作者
Chung, Cheng-Ho [1 ,2 ]
Hao, Ergeng
Piran, Ron [3 ]
Keinan, Ehud [3 ]
Levine, Fred
机构
[1] Sanford Burnham Med Res Inst, Sanford Burnham Inst Grad Program, La Jolla, CA USA
[2] Mackay Mem Hosp, Dept Med, Div Endocrinol & Metab, Taipei, Taiwan
[3] Scripps Res Inst, La Jolla, CA 92037 USA
基金
美国国家科学基金会;
关键词
Diabetes; Regeneration; Stem cell; Progenitor; MOUSE PANCREAS; IN-VIVO; DIFFERENTIATION; REGENERATION; PROGENITORS; EXPRESSION; BIRTH;
D O I
10.1002/stem.482
中图分类号
Q813 [细胞工程];
学科分类号
摘要
Because type 1 and type 2 diabetes are characterized by loss of beta-cells, beta-cell regeneration has garnered great interest as an approach to diabetes therapy. Here, we developed a new model of beta-cell regeneration, combining pancreatic duct ligation (PDL) with elimination of preexisting beta-cells with alloxan. In this model, in which virtually all beta-cells observed are neogenic, large numbers of beta-cells were generated within 2 weeks. Strikingly, the neogenic beta-cells arose primarily from alpha-cells. alpha-cell proliferation was prominent following PDL plus alloxan, providing a large pool of precursors, but we found that beta-cells could form from alpha-cells by direct conversion with or without intervening cell division. Thus, classical asymmetric division was not a required feature of the process of alpha-to beta-cell conversion. Intermediate cells coexpressing alpha-cell-and beta-cell-specific markers appeared within the first week following PDL plus alloxan, declining gradually in number by 2 weeks as beta-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 alpha-cells as beta-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 alpha-to beta-cell conversion that will be required for eventual clinical translation as a therapy for diabetes. STEM CELLS 2010;28:1630-1638
引用
收藏
页码:1630 / 1638
页数:9
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