Institute of Biomechanics and Medical Engineering, Department of Engineering Mechanics, School of Aerospace Engineering, Tsinghua University, Beijing, 100084, China.
Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, 325000, China.
Nat Commun. 2023 Sep 27;14(1):6016. doi: 10.1038/s41467-023-41760-2.
Region-specific gut spheroids are precursors for gastrointestinal and pulmonary organoids that hold great promise for fundamental studies and translations. However, efficient production of gut spheroids remains challenging due to a lack of control and mechanistic understanding of gut spheroid morphogenesis. Here, we report an efficient biomaterial system, termed micropatterned gut spheroid generator (μGSG), to generate gut spheroids from human pluripotent stem cells through mechanically enhanced tissue morphogenesis. We show that μGSG enhances the biogenesis of gut spheroids independent of micropattern shape and size; instead, mechanically enforced cell multilayering and crowding is demonstrated as a general, geometry-insensitive mechanism that is necessary and sufficient for promoting spheroid formation. Combining experimental findings and an active-phase-field morphomechanics theory, our study further reveals an instability-driven mechanism and a mechanosensitive phase diagram governing spheroid pearling and fission in μGSG. This work unveils mechanobiological paradigms based on tissue architecture and surface tension for controlling tissue morphogenesis and advancing organoid technology.
区域特异性肠道球体是胃肠道和肺类器官的前体细胞，它们在基础研究和转化方面具有很大的潜力。然而，由于缺乏对肠道球体形态发生的控制和机制理解，高效生产肠道球体仍然具有挑战性。在这里，我们报告了一种高效的生物材料系统，称为微图案肠道球体发生器（μGSG），通过机械增强组织形态发生从人多能干细胞中生成肠道球体。我们表明，μGSG 增强了肠道球体的生物发生，而与微图案的形状和大小无关；相反，强制的细胞多层化和拥挤被证明是一种普遍的、与几何形状无关的机制，对于促进球体形成是必要和充分的。结合实验结果和主动相场形态力学理论，我们的研究进一步揭示了一个由不稳定性驱动的机制和一个机械敏感的相图，该相图控制着 μGSG 中的球体珍珠化和分裂。这项工作揭示了基于组织架构和表面张力的机械生物学范例，用于控制组织形态发生和推进类器官技术。
