The interplay between pancreatic epithelium and the surrounding microenvironment is pivotal for pancreas formation and differentiation as well as adult organ homeostasis. The mesenchyme is the main component of the embryonic pancreatic microenvironment, yet its cellular identity is broadly defined, and whether it comprises functionally distinct cell subsets is not known. Using genetic lineage tracing, transcriptome, and functional studies, we identified mesenchymal populations with different roles during pancreatic development. Moreover, we showed that Pbx transcription factors act within the mouse pancreatic mesenchyme to define a pro-endocrine specialized niche. Pbx directs differentiation of endocrine progenitors into insulin- and glucagon-positive cells through non-cell-autonomous regulation of ECM-integrin interactions and soluble molecules. Next, we measured functional conservation between mouse and human pancreatic mesenchyme by testing identified mesenchymal factors in an iPSC-based differentiation model. Our findings provide insights into how lineage-specific crosstalk between epithelium and neighboring mesenchymal cells underpin the generation of different pancreatic cell types.

胰腺上皮与周围微环境之间的相互作用对于胰腺的形成和分化以及成人器官稳态至关重要。间充质是胚胎胰腺微环境的主要组成部分，但其细胞特性被广泛定义，并且其是否包含功能不同的细胞亚群尚不清楚。通过遗传谱系追踪、转录组和功能研究，我们确定了在胰腺发育过程中具有不同作用的间充质群体。此外，我们还发现 Pbx 转录因子在小鼠胰腺间质内发挥作用，定义了一个促内分泌的专门生态位。 Pbx 通过 ECM-整合素相互作用和可溶性分子的非细胞自主调节，引导内分泌祖细胞分化为胰岛素和胰高血糖素阳性细胞。接下来，我们通过在基于 iPSC 的分化模型中测试已识别的间充质因子来测量小鼠和人类胰腺间充质之间的功能保守性。我们的研究结果提供了关于上皮细胞和邻近间充质细胞之间的谱系特异性串扰如何支持不同胰腺细胞类型生成的见解。