Cell proliferation is fundamental for almost all stages of development and differentiation that require an increase in cell number. Although cell cycle phase has been associated with differentiation, the actual process of proliferation has not been considered as having a specific role. Here we exploit human embryonic stem cell-derived endodermal progenitors that we find are an in vitro model for the ventral foregut. These cells exhibit expansion-dependent increases in differentiation efficiency to pancreatic progenitors that are linked to organ-specific enhancer priming at the level of chromatin accessibility and the decommissioning of lineage-inappropriate enhancers. Our findings suggest that cell proliferation in embryonic development is about more than tissue expansion; it is required to ensure equilibration of gene regulatory networks allowing cells to become primed for future differentiation. Expansion of lineage-specific intermediates may therefore be an important step in achieving high-fidelity in vitro differentiation.

细胞增殖是几乎所有需要增加细胞数量的发育和分化阶段的基础。尽管细胞周期阶段与分化相关，但实际的增殖过程并未被认为具有特定的作用。在这里，我们利用人类胚胎干细胞衍生的内胚层祖细胞，我们发现它是腹侧前肠的体外模型。这些细胞对胰腺祖细胞的分化效率表现出扩增依赖性的增加，这与染色质可及性水平上的器官特异性增强子启动和谱系不适当增强子的停用有关。我们的研究结果表明，胚胎发育中的细胞增殖不仅仅涉及组织扩张；它还涉及细胞增殖。它需要确保基因调控网络的平衡，使细胞为未来的分化做好准备。因此，谱系特异性中间体的扩展可能是实现高保真体外分化的重要一步。