Parameterized Computational Framework for the Description and Design of Genetic Circuits of Morphogenesis Based on Contact-Dependent Signaling and Changes in Cell–Cell Adhesion

Synthetic development is a nascent
field of research that uses
the tools of synthetic biology to design genetic programs directing
cellular patterning and morphogenesis in higher eukaryotic cells,
such as mammalian cells. One specific example of such synthetic genetic
programs was based on cell–cell contact-dependent signaling
using synthetic Notch pathways and was shown to drive the formation
of multilayered spheroids by modulating cell–cell adhesion via differential expression of cadherin family proteins
in a mouse fibroblast cell line (L929). The design method for these
genetic programs relied on trial and error, which limited the number
of possible circuits and parameter ranges that could be explored.
Here, we build a parameterized computational framework that, given
a cell–cell communication network driving changes in cell adhesion
and initial conditions as inputs, predicts developmental trajectories.
We first built a general computational framework where contact-dependent
cell–cell signaling networks and changes in cell–cell
adhesion could be designed in a modular fashion. We then used a set
of available in vitro results (that we call the “training
set” in analogy to similar pipelines in the machine learning
field) to parameterize the computational model with values for adhesion
and signaling. We then show that this parameterized model can qualitatively
predict experimental results from a “testing set” of
available in vitro data that varied the genetic network
in terms of adhesion combinations, initial number of cells, and even
changes to the network architecture. Finally, this parameterized model
is used to recommend novel network implementation for the formation
of a four-layered structure that has not been reported previously.
The framework that we develop here could function as a testing ground
to identify the reachable space of morphologies that can be obtained
by controlling contact-dependent cell–cell communications and
adhesion with these molecular tools and in this cellular system. Additionally,
we discuss how the model could be expanded to include other forms
of communication or effectors for the computational design of the
next generation of synthetic developmental trajectories.