Differentiation of human embryonic stem cells into pancreatic β cells holds great promise for the treatment of diabetes. Recent advances have led to the production of glucose-responsive insulin-secreting cells in vitro, but resulting cells remain less mature than their adult primary β cell counterparts. The barrier(s) to in vitro β cell maturation are unclear. Here, we evaluated a potential role for microRNAs. MicroRNA profiling showed high expression of let-7 family microRNAs in vivo, but not in in vitro differentiated β cells. Reduced levels of let-7 in vitro were associated with increased levels of the RNA binding protein LIN28B, a negative regulator of let-7 biogenesis. Ablation of LIN28B during human embryonic stem cell (hESC) differentiation toward β cells led to a more mature glucose-stimulated insulin secretion profile and the suppression of juvenile-specific genes. However, let-7 overexpression had little effect. These results uncover LIN28B as a modulator of β cell maturation in vitro.

人胚胎干细胞向胰腺β细胞的分化具有治疗糖尿病的巨大希望。最近的进展已导致体外产生葡萄糖反应性胰岛素分泌细胞，但所得细胞的成熟度仍低于其成人原代β细胞。体外β细胞成熟的障碍尚不清楚。在这里，我们评估了microRNA的潜在作用。MicroRNA分析显示let-7家族microRNA在体内高表达，但在体外分化的β细胞中却没有。降低let-7的体外水平它们与RNA结合蛋白LIN28B（let-7生物发生的负调节剂）水平升高有关。在人类胚胎干细胞（hESC）向β细胞分化过程中LIN28B的消融导致更成熟的葡萄糖刺激的胰岛素分泌特征和对少年特异性基因的抑制。但是，let-7的过度表达几乎没有效果。这些结果发现LIN28B是体外β细胞成熟的调节剂。