在发育过程中，细胞经历对称破缺，分化成自组织的复杂结构。然而，目前鲜有工具可以在可控和耦合的方式下重现这些行为。我们在此研究中构建了一种通过小分子调控的随机重组酶基因开关，以诱导可编程的对称破缺、细胞未来命运的承诺和形态自组织。诱导物决定了细胞承诺概率，从而根据诱导物剂量生成可调控的亚群体。我们利用此开关来控制承诺于各命运的细胞的细胞间粘附特性。我们从单克隆细胞群体中生成了各种三维形态，并开发了一个与实验结果高度一致的计算模型，从而得到了细胞间粘附强度与下游形态之间关系的新的定量洞察。我们预计，可编程的对称破缺、生成精确和可调节的亚群体比例，并与结构形态耦合，将成为复杂组织和器官工程的工具箱的一个重要组成部分。版权所有 © 2023 依图公司。保留所有权利。

During development, cells undergo symmetry breaking into differentiated subpopulations that self-organize into complex structures.1,2,3,4,5 However, few tools exist to recapitulate these behaviors in a controllable and coupled manner.6,7,8,9 Here, we engineer a stochastic recombinase genetic switch tunable by small molecules to induce programmable symmetry breaking, commitment to downstream cell fates, and morphological self-organization. Inducers determine commitment probabilities, generating tunable subpopulations as a function of inducer dosage. We use this switch to control the cell-cell adhesion properties of cells committed to each fate.10,11 We generate a wide variety of 3D morphologies from a monoclonal population and develop a computational model showing high concordance with experimental results, yielding new quantitative insights into the relationship between cell-cell adhesion strengths and downstream morphologies. We expect that programmable symmetry breaking, generating precise and tunable subpopulation ratios and coupled to structure formation, will serve as an integral component of the toolbox for complex tissue and organoid engineering.Copyright © 2023 Elsevier Inc. All rights reserved.