Cell Density Unlocks Predictable Patterns in Synthetic Tissues

In recent research published in Nature Communications, scientists investigated the role of cell density – how closely cells are packed in a given space – in forming multicellular structures. The study was conducted by a team from the University of Southern California (USC) and the California Institute of Technology (Caltech). Through computational modeling and laboratory experiments, researchers demonstrated how varying cell densities influence the organization of mouse cells into complex patterns.

“This paper represents progress towards our big picture goal of engineering synthetic tissues.”
Dr. Leonardo Morsut

Engineering synthetic tissues with cellular circuits

The study utilized genetically engineered mouse cells, including connective tissue cells and stem cells. These cells were equipped with a synthetic cellular communication system, referred to as a "genetic circuit," which included synNotch proteins. SynNotch is a surface protein sensor that responds to external signals by activating specific genetic programs. In these experiments, synNotch was used to produce green fluorescence, allowing researchers to observe how cells organize into patterns.

By controlling cell density, the scientists achieved distinct and predictable patterns, such as rings of fluorescence radiating from a central point. This approach revealed that cell density significantly affects the outcomes of cellular patterning, even among genetically identical cells.

“We would see different outcomes of the patterning when we would start with genetically identical cells in different numbers. So that was puzzling at the beginning. I remember Marco came in and told me once that the experiment worked, but only in half of the plate. And when we looked at it more carefully, we started seeing that there was a gradient of cell density that seemed to correlate with differences in patterning.”

Dr. Leonardo Morsut

Computational modeling clarifies complex cell interactions

To better understand these phenomena, researchers developed computational models. These models successfully predicted cellular behavior, such as the impact of proliferation rates and signaling on pattern formation. Guided by these simulations, the team refined their experiments, confirming that cell density could direct the development of specific patterns over time.

Unexpected findings about cell density and synNotch

The study also uncovered that high cell density caused stress, leading to the breakdown of surface sensors like synNotch. This reduced the sensor's effectiveness in triggering patterns. Such findings suggest that cell density serves as a fundamental tool, not only for engineering synthetic tissues but also for understanding natural tissue development.

The research highlights the potential to use cell density in conjunction with genetic circuits to build synthetic tissues for regenerative medicine, with applications ranging from drug testing to transplantation.

Reference: Santorelli M, Bhamidipati PS, Courte J, et al. Control of spatio-temporal patterning via cell growth in a multicellular synthetic gene circuit. Nat Comm. 2024;15(1):9867. doi: 10.1038/s41467-024-53078-8

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