Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Program in Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Cell Syst. 2023 Sep 20;14(9):806-818.e5. doi: 10.1016/j.cels.2023.08.001. Epub 2023 Sep 8.
During development, cells undergo symmetry breaking into differentiated subpopulations that self-organize into complex structures. However, few tools exist to recapitulate these behaviors in a controllable and coupled manner. 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. 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.
在发育过程中，细胞经历对称性破缺，分化为亚群，这些亚群自我组织成复杂的结构。然而，目前很少有工具能够以可控和耦合的方式再现这些行为。在这里，我们设计了一种受小分子调控的随机重组酶遗传开关，以诱导可编程的对称性破缺、下游细胞命运的确定和形态的自我组织。诱导剂决定了确定的概率，从而产生随诱导剂剂量变化的可调亚群。我们使用这个开关来控制每个命运所确定的细胞的细胞间黏附特性。我们从单克隆群体中生成了各种各样的 3D 形态，并开发了一个计算模型，该模型与实验结果高度一致，为细胞间黏附强度与下游形态之间的关系提供了新的定量见解。我们预计，可编程的对称性破缺，产生精确和可调的亚群比例，并与结构形成相耦合，将成为复杂组织和类器官工程工具包的一个组成部分。
