The pancreas originates from two epithelial evaginations of the foregut, which consist of multipotent epithelial progenitors that organize into a complex tubular epithelial network. The trunk domain of each epithelial branch consists of bipotent pancreatic progenitors (bi-PPs) that give rise to both duct and endocrine lineages, whereas the tips give rise to acinar cells1. Here we identify the extrinsic and intrinsic signalling mechanisms that coordinate the fate-determining transcriptional events underlying these lineage decisions1,2. Single-cell analysis of pancreatic bipotent pancreatic progenitors derived from human embryonic stem cells reveal that cell confinement is a prerequisite for endocrine specification, whereas spreading drives the progenitors towards a ductal fate. Mechanistic studies identify the interaction of extracellular matrix (ECM) with integrin α5 as the extracellular cue that cell-autonomously, via the F-actin–YAP1–Notch mechanosignalling axis, controls the fate of bipotent pancreatic progenitors. Whereas ECM–integrin α5 signalling promotes differentiation towards the duct lineage, endocrinogenesis is stimulated when this signalling cascade is disrupted. This cascade can be disrupted pharmacologically or genetically to convert bipotent pancreatic progenitors derived from human embryonic stem cells to hormone-producing islet cells. Our findings identify the cell-extrinsic and intrinsic mechanotransduction pathway that acts as gatekeeper in the fate decisions of bipotent pancreatic progenitors in the developing pancreas.Single-cell analysis reveals that interactions with the extracellular matrix via integrin α5 and mechanotransducer YAP1 determine whether pancreatic progenitors develop along the duct or endocrine lineages.

中文翻译：

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通过整合素的机械信号传导指导胰腺祖细胞的命运决定

胰腺起源于前肠的两个上皮外翻，由多能上皮祖细胞组成，这些祖细胞组织成复杂的管状上皮网络。每个上皮分支的主干域由产生导管和内分泌谱系的双能胰腺祖细胞 (bi-PPs) 组成，而尖端产生腺泡细胞。在这里，我们确定了协调这些谱系决定背后的决定命运的转录事件的外在和内在信号机制1,2。来自人类胚胎干细胞的胰腺双能胰腺祖细胞的单细胞分析表明，细胞限制是内分泌规范的先决条件，而扩散则驱使祖细胞走向导管命运。机制研究确定细胞外基质 (ECM) 与整合素 α5 的相互作用作为细胞外线索，细胞自主地通过 F-肌动蛋白-YAP1-Notch 机械信号轴控制双能胰腺祖细胞的命运。ECM-integrin α5 信号促进向导管谱系分化，当这种信号级联被破坏时，内分泌发生会受到刺激。这种级联可以在药理学或遗传学上被破坏，以将源自人类胚胎干细胞的双能胰腺祖细胞转化为产生激素的胰岛细胞。我们的研究结果确定了细胞外在和内在机械转导途径，该途径在发育中的胰腺中双能胰腺祖细胞的命运决定中充当守门人。