In a remarkable study published in Nature Communications, researchers from USC and Caltech explored the role of cell density in tissue formation. This discovery could significantly impact the future of regenerative medicine and synthetic tissue engineering.
In a ground-breaking study published in Nature Communications, scientists from USC Stem Cell and Caltech have revealed crucial insights into how cell density influences the formation of multicellular structures, potentially paving the way for advancements in synthetic tissue engineering and regenerative medicine.
“This paper represents progress towards our big picture goal of engineering synthetic tissues,” Leonardo Morsut, an assistant professor of stem cell biology and regenerative medicine at the Keck School of Medicine of USC who holds a joint appointment with the Biomedical Engineering department at the USC Viterbi School of Engineering, said in a news release. “Synthetic tissues could have endless medical applications, ranging from testing potential drugs or therapies to providing grafts or transplants for patients.”
The collaborative research, led by Morsut and Matthew Thomson, an assistant professor of computational biology at Caltech, focused on the impacts of cell density — essentially how tightly cells are packed in a given space — on tissue formation. Their efforts combined computational models with laboratory experiments to manipulate how mouse cells self-organize into complex structures.
Using two types of engineered mouse cells, connective tissue cells and stem cells, the team employed a synthetic cellular communication system known as “synNotch” to control this development. SynNotch, a protein engineered into cells, acts as a sensor that activates specific genes in response to external signals.
In these experiments, the activation system included green fluorescence, making it simpler to observe and manipulate cellular patterns.
An unexpected observation during the experiments revealed that cell density played a more crucial role than initially thought.
“We would see different outcomes of the patterning when we would start with genetically identical cells in different numbers,” added Morsut.
This variability led to the discovery that above certain densities, synNotch had diminished effects, and cells did not form expected patterns. This challenge was further complicated by the dynamic nature of cell proliferation, which continually altered the cell density.
Co-first author Pranav S. Bhamidipati took this puzzle to the computational realm, creating a model to predict and clarify the complex interactions at play.
“For me, this was one of the first times in my life where computational modeling has been able to predict behaviors that look like what actually happens in the cells,” Thomson said in the news release.
Guided by these predictive models, the researchers were able to manipulate cell density to generate specific, predictable fluorescent patterns over time.
The breakthrough came when co-first author Josquin Courte discovered that greater cell density leads to stress, which accelerates the breakdown of cell surface sensors like synNotch, thus demonstrating that cell density can broadly guide cellular construction.
“Nature has relied on cell density in conjunction with genetic circuits to generate the remarkable diversity of multicellular structures, tissues, and organs,” Morsut added. “Now we can co-opt this same strategy to advance our efforts to build synthetic multicellular structures — and eventually tissues and organs—for regenerative medicine.”
This cutting-edge research highlights the importance of cell density in tissue engineering, marking a pivotal advancement that brings science one step closer to revolutionizing medical treatments through synthetic tissues.