Conversion of adult pancreatic α-cells to β-cells after extreme β-cell loss

摘要

Pancreatic insulin-producing β-cells have a long lifespan, such that in healthy conditions they replicate little during a lifetime. Nevertheless, they show increased self-duplication after increased metabolic demand or after injury (that is, p-cell loss). It is not known whether adult mammals can differentiate (regenerate) new β-cells after extreme, total p-cell loss, as in diabetes. This would indicate differentiation from precursors or another heterologous (non-(3-cell) source. Here we show p-cell regeneration in a transgenic model of diphtheria-toxin-induced acute selective near-total p-cell ablation. If given insulin, the mice survived and showed p-cell mass augmentation with time. Lineage-tracing to label the glucagon-producing a-cells before p-cell ablation tracked large fractions of regenerated β-cells as deriving from a-cells, revealing a previously disregarded degree of pancreatic cell plasticity. Such inter-endocrine spontaneous adult cell conversion could be harnessed towards methods of producing β-cells for diabetes therapies, either in differentiation settings in vitro or in induced regeneration.%胰腺中产生胰岛素的β-细胞寿命长，在其生rn命周期中几乎不复制，但在受伤时或有代谢需rn求时则会复制。对β-细胞几乎被完全去除的rn一个转基冈小鼠模型所做研究表明，成年α-rn细胞(正常情况下负责产生肽荷尔蒙升血糖素)rn可以被自发地重新编程为β-细胞。关于胰腺rn细胞弹性的这一意外发现，让我们看到了糖尿rn病的可能治疗方法；要么通过差异化环境来在rn体外生成细胞；要么在体内诱导细胞再生。而rn目，关于选择性杀死细胞及非选择性地全部杀rn死细胞的新模型的建立，可能会显示其他器官rn中以前未被识别出的细胞弹性。