Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
Nat Commun. 2024 Nov 19;15(1):9867. doi: 10.1038/s41467-024-53078-8.
A major goal in synthetic development is to build gene regulatory circuits that control patterning. In natural development, an interplay between mechanical and chemical communication shapes the dynamics of multicellular gene regulatory circuits. For synthetic circuits, how non-genetic properties of the growth environment impact circuit behavior remains poorly explored. Here, we first describe an occurrence of mechano-chemical coupling in synthetic Notch (synNotch) patterning circuits: high cell density decreases synNotch-gated gene expression in different cellular systems in vitro. We then construct, both in vitro and in silico, a synNotch-based signal propagation circuit whose outcome can be regulated by cell density. Spatial and temporal patterning outcomes of this circuit can be predicted and controlled via modulation of cell proliferation, initial cell density, and/or spatial distribution of cell density. Our work demonstrates that synthetic patterning circuit outcome can be controlled via cellular growth, providing a means for programming multicellular circuit patterning outcomes.
合成发展的主要目标是构建控制模式的基因调控电路。在自然发育过程中，机械和化学通讯之间的相互作用塑造了多细胞基因调控电路的动力学。对于合成电路，生长环境的非遗传特性如何影响电路行为仍未得到很好的探索。在这里，我们首先描述了合成 Notch（synNotch）模式形成电路中机械-化学偶联的发生：高密度降低了不同细胞系统中 synNotch 门控基因的表达。然后，我们构建了基于 synNotch 的信号传播电路，该电路的输出可以通过细胞密度进行调节。通过调节细胞增殖、初始细胞密度和/或细胞密度的空间分布，可以预测和控制该电路的时空模式形成结果。我们的工作表明，通过细胞生长可以控制合成模式形成电路的结果，为编程多细胞电路模式形成结果提供了一种方法。
