Nature Versus Nurture In Silico

Neighbor cells affect stem cell differentiation in computer simulation

Every generation, a few nonconformists crop up in tissue cultures of genetically identical cells. The question is: are the wayward simply born that way, or did something in the environment affect them? “You have these two possibilities—intrinsic or extrinsic, nature or nurture,” says Andras Paldi, PhD, a biologist at Genethon in France. Now, Paldi and his colleagues have modeled such cultured cells to determine whether extrinsic or intrinsic influences play a key role in the spontaneous emergence of phenotypic variation. It turns out that for spatial patterns beyond randomness to arise, there has to be some effect of sensing neighboring cells—i.e., extrinsic factors must play a role. And the extrinsic model resembles results seen in real cells. The work appears in April in PLoS One.


Paldi’s work was motivated in part by the open question among stem cell biologists of what triggers a stem cell to differentiate. Why, in the same warm spot, getting the same rich media, do some cells differentiate and others stay stem cells? It is commonly assumed that this is because the decision to differentiate is intrinsic—that is, purely random.


Agent-based computer models predict the pattern (left) produced when genetically identical cells have an inherent probability of changing (from green to red and vice versa), and the pattern (right) produced when cells are triggered to change by an extrinsic factor, such as cell density. Top images represent exponential growth;  bottom are at equilibrium. Courtesy of Andras Paldi.To test that assumption, Paldi’s group started by designing two simple, multi-agent based models of a tissue culture plate. In each model, all cells act independently and can switch between two cell types: A or B. In the “extrinsic” model, A cells turn into B cells when it gets crowded, and back to A cells when they have more space. In the “intrinsic” model, each cell has fixed probabilities of switching from A to B and back again.


When the scientists ran the models, they found each produces a stable, heterogeneous population, yet they differ in the cell patterns. The intrinsic model predicts lone A cells distributed evenly throughout a largely B population. Extrinsic predicts that the A cells will cluster. The result held even though the cells were allowed to migrate.


This pattern difference allowed the researchers to compare their computational simulation with real cells. Using a muscle cell line that can switch between two distinct phenotypes, a stem-cell like progenitor state and a differentiated state, they found that the cell pattern mostly resembles that of the extrinsic model. Many of the rare, stem-cell like cells cluster; a few are solitary.


What’s important here, Paldi says, is that they find environment playing a role—a significant one. In the case of stem (progenitor) cells, it means neighbor cells can affect the differentiation process. “The stem cell nature is not an intrinsic property of the cell,” he says. “It is a property of the whole cell population.” Paldi further believes the work supports the effort to find a way of converting adult, differentiated cells into stem cells (and avoid the need for harvesting embryonic stem cells)—a possibility that has not just scientific, but social and political implications as well.


Christa Muller-Sieburg, PhD, however, disputes that scientific conclusion. “The idea that mature cells can turn into stem cells is very attractive to many modelers but has little support through experimental data,” says the professor at the Sidney Kimmel Cancer Center.


Sui Huang, MD, PhD, at Children’s Hospital Boston, would have liked to see Paldi’s group perturb the cell line or the culture to confirm their model. But both he and Muller-Sieburg believe the study addressed an important question, that of heterogeneity of a genetically identical population of cells. And, says Huang, it certainly “contributes to the discussion in the community.”



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