Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure.
Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure.
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DOI：
10.1016/j.cell.2012.07.029
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发表时间：
2012-09-14
期刊：
影响因子：
64.5
通讯作者：
Accili D
中科院分区：
文献类型：
--
作者：
Talchai C;Xuan S;Lin HV;Sussel L;Accili D
糖尿病与β细胞衰竭有关。但尚不清楚后者是由于β细胞数量减少还是功能减少。fox01整合了β细胞增殖和适应性β细胞功能。我们利用β细胞中缺乏fox01的小鼠，研究了这两个过程对β细胞功能障碍的贡献。FoxO1消融引起高血糖，并在生理性应激（如多胎和衰老）后减少β细胞质量。令人惊讶的是，谱系追踪实验表明β细胞质量的损失是由于β细胞去分化，而不是死亡。去分化的β细胞恢复为表达Neurogenin3、Oct4、Nanog和L-Myc的祖细胞样细胞。fox01缺陷的β细胞亚群采用α细胞命运，导致高胰高血糖素血症。引人注目的是，我们将相同的事件序列确定为不同小鼠糖尿病模型的特征。我们提出，在β细胞衰竭的自然史中，去分化优于内分泌细胞死亡，并建议治疗β细胞功能障碍应该恢复分化，而不是促进β细胞复制。
Diabetes is associated with β-cell failure. But it remains unclear whether the latter results from reduced β-cell number or function. FoxO1 integrates β-cell proliferation with adaptive β-cell function. We interrogated the contribution of these two processes to β-cell dysfunction, using mice lacking FoxO1 in β-cells. FoxO1 ablation caused hyperglycemia with reduced β-cell mass following physiologic stress, such as multiparity and aging. Surprisingly, lineage-tracing experiments demonstrated that loss of β-cell mass was due to β-cell dedifferentiation, not death. Dedifferentiated β-cells reverted to progenitor-like cells expressing Neurogenin3, Oct4, Nanog, and L-Myc. A subset of FoxO1-deficient β-cells adopted the α-cell fate, resulting in hyperglucagonemia. Strikingly, we identify the same sequence of events as a feature of different models of murine diabetes. We propose that dedifferentiation trumps endocrine cell death in the natural history of β-cell failure, and suggest that treatment of β-cell dysfunction should restore differentiation, rather than promoting β-cell replication.
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