Water makes up around 60 percent of the human body. More than half of this water sloshes around inside the cells that make up organs and tissues. Much of the remaining water flows in the nooks and crannies between cells, much like seawater between grains of sand.Now, MIT engineers have found that this “intercellular” fluid plays a major role in how tissues respond when squeezed, pressed, or physically deformed. Their findings could help scientists understand how cells, tissues, and organs physically adapt to conditions such as aging, cancer, diabetes, and certain neuromuscular diseases.In a paper appearing today in Nature Physics, the researchers show that when a tissue is pressed or squeezed, it is more compliant and relaxes more quickly when the fluid between its cells flows easily. When the cells are packed together and there is less room for intercellular flow, the tissue as a whole is stiffer and resists being pressed or squeezed.The findings challenge conventional wisdom, which has assumed that a tissue’s compliance depends mainly on what’s inside, rather than around, a cell. Now that the researchers have shown that intercellular flow determines how tissues will adapt to physical forces, the results can be applied to understand a wide range of physiological conditions, including how muscles withstand exercise and recover from injury, and how a tissue’s physical adaptability may affect the progression of aging, cancer, and other medical conditions.The team envisions the results could also inform the design of artificial tissues and organs. For instance, in engineering artificial tissue, scientists might optimize intercellular flow within the tissue to improve its function or resilience. The researchers suspect that intercellular flow could also be a route for delivering nutrients or therapies, either to heal a tissue or eradicate a tumor.“People know there is a lot of fluid between cells in tissues, but how important that is, in particular in tissue deformation, is completely ignored,” says Ming Guo, associate professor of mechanical engineering at MIT. “Now we really show we can observe this flow. And as the tissue deforms, flow between cells dominates the behavior. So, let’s pay attention to this when we study diseases and engineer tissues.”Guo is a co-author of the new study, which includes lead author and MIT postdoc Fan Liu PhD ’24, along with Bo Gao and Hui Li of Beijing Normal University, and Liran Lei and Shuainan Liu of Peking Union Medical College.Pressed and squeezedThe tissues and organs in our body are constantly undergoing physical deformations, from the large stretch and strain of muscles during motion to the small and steady contractions of the heart. In some cases, how easily tissues adapt to deformation can relate to how quickly a person can recover from, for instance, an allergic reaction, a sports injury, or a brain stroke. However, exactly what sets a tissue’s response to deformation is largely unknown.Guo and his group at MIT looked into the mechanics of tissue deformation, and the role of intercellular flow in particular, following a study they published in 2020. In that study, they focused on tumors and observed the way in which fluid can flow from the center of a tumor out to its edges, through the cracks and crevices between individual tumor cells. They found that when a tumor was squeezed or pressed, the intercellular flow increased, acting as a conveyor belt to transport fluid from the center to the edges. Intercellular flow, they found, could fuel tumor invasion into surrounding regions.In their new study, the team looked to see what role this intercellular flow might play in other, noncancerous tissues.“Whether you allow the fluid to flow between cells or not seems to have a major impact,” Guo says. “So we decided to look beyond tumors to see how this flow influences how other tissues respond to deformation.”A fluid pancakeGuo, Liu, and their colleagues studied the intercellular flow in a variety of biological tissues, including cells derived from pancreatic tissue. They carried out experiments in which they first cultured small clusters of tissue, each measuring less than a quarter of a millimeter wide and numbering tens of thousands of individual cells. They placed each tissue cluster in a custom-designed testing platform that the team built specifically for the study.“These microtissue samples are in this sweet zone where they are too large to see with atomic force microscopy techniques and too small for bulkier devices,” Guo says. “So, we decided to build a device.”The researchers adapted a high-precision microbalance that measures minute changes in weight. They combined this with a step motor that is designed to press down on a sample with nanometer precision. The team placed tissue clusters one at a time on the balance and recorded each cluster’s changing weight as it relaxed from a sphere into the shape of a pancake in response to the compression. The team also took videos of the clusters as they were squeezed.For each type of tissue, the team made clusters of varying sizes. They reasoned that if the tissue’s response is ruled by the flow between cells, then the bigger a tissue, the longer it should take for water to seep through, and therefore, the longer it should take the tissue to relax. It should take the same amount of time, regardless of size, if a tissue’s response is determined by the structure of the tissue rather than fluid.Over multiple experiments with a variety of tissue types and sizes, the team observed a similar trend: The bigger the cluster, the longer it took to relax, indicating that intercellular flow dominates a tissue’s response to deformation.“We show that this intercellular flow is a crucial component to be considered in the fundamental understanding of tissue mechanics and also applications in engineering living systems,” Liu says.Going forward, the team plans to look into how intercellular flow influences brain function, particularly in disorders such as Alzheimer’s disease.“Intercellular or interstitial flow can help you remove waste and deliver nutrients to the brain,” Liu adds. “Enhancing this flow in some cases might be a good thing.”“As this work shows, as we apply pressure to a tissue, fluid will flow,” Guo says. “In the future, we can think of designing ways to massage a tissue to allow fluid to transport nutrients between cells.”
