Larrañaga Enara, Marin-Riera Miquel, Abad-Lázaro Aina, Bartolomé-Català David, Otero Aitor, Fernández-Majada Vanesa, Batlle Eduard, Sharpe James, Ojosnegros Samuel, Comelles Jordi, Martinez Elena
Biomimetic Systems for Cell Engineering Laboratory, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
European Molecular Biology Laboratory (EMBL), Barcelona, Spain.
Nat Commun. 2025 Jan 3;16(1):382. doi: 10.1038/s41467-024-55651-7.
Intestinal epithelial cells are segregated into proliferative crypts and differentiated regions. This organization relies on specific signals, including Wnt3a, which regulates cell proliferation within crypts, and Eph/Ephrin, which dictates cell positioning along the crypt-villus axis. However, studying how the spatial distributions of these signals influences crypt-villus organization is challenging both in vitro and in vivo. Here we show that micropatterns of Wnt3a can govern the size, shape and long-range organization of crypts in vitro. By adjusting the spacing between Wnt3a ligand patterns at the microscale over large surfaces, we override endogenous Wnt3a to precisely control the distribution and long-range order of crypt-like regions in primary epithelial monolayers. Additionally, an agent-based model integrating Wnt3a/BMP feedback and Eph/Ephrin repulsion effectively replicates experimental tissue compartmentalization, crypt size, shape, and organization. This combined experimental and computational approach offers a framework to study how signaling pathways help organize intestinal epithelial tissue.
肠上皮细胞被分隔为增殖性隐窝和分化区域。这种组织结构依赖于特定信号，包括调节隐窝内细胞增殖的Wnt3a，以及决定细胞沿隐窝 - 绒毛轴定位的Eph/ Ephrin。然而，研究这些信号的空间分布如何影响隐窝 - 绒毛组织在体外和体内都是具有挑战性的。在这里，我们表明Wnt3a的微图案可以在体外控制隐窝的大小、形状和长程组织。通过在大表面上在微观尺度调整Wnt3a配体图案之间的间距，我们超越内源性Wnt3a，精确控制原代上皮单层中隐窝样区域的分布和长程秩序。此外，一个整合Wnt3a/BMP反馈和Eph/ Ephrin排斥的基于主体的模型有效地复制了实验性组织分区、隐窝大小、形状和组织。这种实验与计算相结合的方法提供了一个框架，用于研究信号通路如何帮助组织肠上皮组织。
