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Abstract
Advances in genetic engineering technologies have allowed the construction of artificial genetic circuits, which have been used to generate spatial patterns of differential gene expression. However, the question of how cells can be programmed, and how complex the rules need to be, to achieve a desired tissue morphology has received less attention. Here, we address these questions by developing a mathematical model to study how cells can collectively grow into clusters with different structural morphologies by secreting diffusible signals that can influence cellular growth rates. We formulate how growth regulators can be used to control the formation of cellular protrusions and how the range of achievable structures scales with the number of distinct signals. We show that a single growth inhibitor is insufficient for the formation of multiple protrusions but may be achieved with multiple growth inhibitors, and that other types of signals can regulate the shape of protrusion tips. These examples illustrate how our approach could potentially be used to guide the design of regulatory circuits for achieving a desired target structure.
Highlights
A fundamental goal of synthetic developmental biology is to understand how cells can be programmed to generate a desired spatial configuration
How can cells grow into clusters with certain structural features, and how complex do the corresponding growth regulatory mechanisms need to be? Here, we use a model where cells can secrete diffusible signals, and both the secretion rates of these signals as well as the growth rate of cells can be regulated based on their local chemical environment
We explore questions such as how can we program the growth of a single protrusion, and when is it possible to grow multiple protrusions or a protrusion with a sharp tip
Summary
A fundamental goal of synthetic developmental biology is to understand how cells can be programmed to generate a desired spatial configuration. Global information that needs to be accessible for cellular decision making must be encoded in their local environment. Recent advances in genetic engineering technologies have made it possible to encode desired sets of rules within the genetic programs of cells, and these have been used to create distinct spatial patterns [1,2,3,4,5]. The use of a synthetic notch receptor system to encode changes in the expression levels of cadherin molecules (in ‘receiver cells’ engineered with receptors that trigger downstream cellular responses when activated) upon contact with another cell type (‘sender cells’ engineered with ligands on cell surface) led to self-organization of clusters with distinct spatial arrangements of different cell types [3, 6]. A graded pattern of signaling activity was obtained by culturing engineered Hedgehog-responding cells next to engineered Hedgehog-secreting cells [4], and Turing-like patterns were generated by reconstituting an activator-inhibitor circuit of two diffusible molecules [5]
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