EVANSTON, Ill. --- A team led by Melody Swartz, assistant professor adjunct of biomedical engineering at Northwestern University and assistant professor at Ecole Polytechnique Federale de Lausanne (EPFL) in Switzerland, has demonstrated that the presence of very slow biological flows affects the extracellular environment in ways that may be critical for tissue formation and cell migration.
The findings -- knowledge that could be immediately used in tissue engineering applications -- are published online this week by the Proceedings of the National Academy of Sciences (PNAS).
A major challenge for tissue engineering is to identify the essential environmental ingredients that cells need in order to communicate, migrate and organize into living tissues. One of these ingredients is the presence, outside the cell, of minute changes in the concentration of special proteins called morphogens. Cells can sense even the tiniest differences in morphogen concentration and will alter their functions accordingly. In embryonic development, stem cells differentiate into organs by means of the actions of morphogens. And even cancer cells can use morphogens to grow, induce a blood supply and metastasize.
Although the concept of cell organization in response to these morphogen gradients is well documented, little is known about how these subtle concentration changes get established in the first place, particularly within the dynamic environment of a real tissue. This research provides evidence that tiny biophysical forces in the extracellular environment may play an important role.
Swartz and her colleagues, including Cara-Lynn Helm, a Ph.D. student at Northwestern and first author on the PNAS paper, have found that slow biophysical flows, such as those that exist between the lymphatic and blood capillaries to help transport macromolecules from blood to tissues, play an important role in the formation of these gradients. They used a computational model developed by Mark Fleury, a Ph.D. student at EPFL, to demonstrate that in the presence of a slow moving flow, cells can set up and even amplify their own morphogen gradients.
“This exquisite system may have evolved as a way for cells to gain better control of their local extracellular surroundings, where they can use the fluid forces that exist in tissues to direct and amplify communication and organization,” said Swartz.
Helm used an in vitro model of capillary formation to demonstrate proof-of-concept that small biophysical flows play a critical role in tissue formation. She placed human blood and lymphatic endothelial cells in an environment containing matrix-bound vascular endothelial growth factor (VEGF) and subjected the system to a very slow externally induced flow.
Without the flow, very little cell organization took place. With the combination of flow and VEGF, the endothelial cells networked and organized, quickly forming capillaries. “Cara gave the cells the right biochemical environment and a physical impetus, and the two conditions combined synergistically, driving the cells to organize into functional structures,” said Swartz.
This research shows clearly that small biophysical forces are among the critical environmental cues that tell cells where to migrate and how to organize into functional tissues. In addition to tissue engineering applications, this discovery could be used to improve our understanding of basic cellular signaling and organizational processes.
“This result can be generalized to any system that is driven by protein gradients that bind to the extracellular matrix,” noted Swartz. “This includes proteins that drive immune cells into the lymphatic system, an important part of the immune response, and others that drive tumor cells into the lymphatic system, where they spread and become deadly. We need to understand these basic processes if we want to design strategies to enhance or inhibit them.”
In addition to Swartz, Helm and Fleury, other authors on the PNAS paper are Andreas H. Zisch, from University Hospital, Zurich, Switzerland; and Federica Boschetti, from Politecnico di Milano, Milan, Italy.
The research was supported by the National Institutes of Health, the Arnold and Mabel Beckman Foundation and the Gebert Ruef Foundation.