Insulin-producing beta cells sourced from pluripotent stem cells hold great potential as a virtually unlimited cell source to treat diabetes. Directed pancreatic differentiation protocols aim to mimic various stimuli present during embryonic development through sequential changes of in vitro culture conditions. This is commonly accomplished by the timed addition of soluble signaling factors, in conjunction with cell-handling steps such as the formation of 3D cell aggregates. Interestingly, when stem cells at the pancreatic progenitor stage are transplanted, they form functional insulin-producing cells, suggesting that in vivo microenvironmental cues promote beta cell specification. Among these cues, biophysical stimuli have only recently emerged in the context of optimizing pancreatic differentiation protocols. This review focuses on studies of cell–microenvironment interactions and their impact on differentiating pancreatic cells when considering cell signaling, cell–cell and cell–ECM interactions. We highlight the development of in vitro cell culture models that allow systematic studies of pancreatic cell mechanobiology in response to extracellular matrix proteins, biomechanical effects, soluble factor modulation of biomechanics, substrate stiffness, fluid flow and topography. Finally, we explore how these new mechanical insights could lead to novel pancreatic differentiation protocols that improve efficiency, maturity, and throughput.

中文翻译：

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从多能前体中产生功能性胰岛样细胞的受发育启发的仿生培养模型

源自多能干细胞的产生胰岛素的β细胞作为治疗糖尿病的几乎无限细胞来源具有巨大潜力。定向胰腺分化方案旨在通过体外培养条件的连续变化来模拟胚胎发育过程中存在的各种刺激。这通常是通过定时添加可溶性信号因子以及细胞处理步骤（如 3D 细胞聚集体的形成）来实现的。有趣的是，当胰腺祖细胞阶段的干细胞被移植时，它们会形成功能性胰岛素产生细胞，这表明体内微环境线索促进了 β 细胞的特化。在这些线索中，生物物理刺激最近才出现在优化胰腺分化方案的背景下。本综述重点研究细胞-微环境相互作用及其在考虑细胞信号传导、细胞-细胞和细胞-ECM 相互作用时对分化胰腺细胞的影响。我们强调了体外细胞培养模型的发展，这些模型允许系统研究胰腺细胞力学生物学以响应细胞外基质蛋白、生物力学效应、生物力学的可溶性因子调节、基质刚度、流体流动和地形。最后，我们探索这些新的机械见解如何导致新的胰腺分化方案，以提高效率、成熟度和吞吐量。我们强调了体外细胞培养模型的发展，这些模型允许系统研究胰腺细胞力学生物学以响应细胞外基质蛋白、生物力学效应、生物力学的可溶性因子调节、基质刚度、流体流动和地形。最后，我们探索这些新的机械见解如何导致新的胰腺分化方案，以提高效率、成熟度和吞吐量。我们强调了体外细胞培养模型的发展，这些模型允许系统研究胰腺细胞力学生物学以响应细胞外基质蛋白、生物力学效应、生物力学的可溶性因子调节、基质刚度、流体流动和地形。最后，我们探索这些新的机械见解如何导致新的胰腺分化方案，以提高效率、成熟度和吞吐量。