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H2O constitutes approximately 60 percent of the human physique. More than half of this liquid swirls around within the cells that form organs and tissues. A significant portion of the remaining fluid traverses the gaps and spaces between cells, akin to seawater moving between grains of sand.
Recently, MIT engineers discovered that this “intercellular” liquid plays a crucial role in how tissues react when compressed, pressed, or physically altered. Their discoveries may assist scientists in comprehending how cells, tissues, and organs physically adjust to circumstances such as aging, cancer, diabetes, and particular neuromuscular disorders.
In a study published today in Nature Physics, the researchers demonstrate that when tissue is compressed or squeezed, it exhibits greater compliance and relaxes swiftly when the fluid amid its cells flows freely. Conversely, when the cells are densely packed with limited intercellular flow, the tissue as a whole becomes more rigid and resists compression.
The results contradict traditional beliefs, which have maintained that a tissue’s compliance relies primarily on the internal contents of a cell, rather than its surroundings. Since the researchers now establish that intercellular flow dictates how tissues adapt to physical forces, these insights can be utilized to better understand a broad spectrum of physiological conditions, including how muscles endure exercise and recuperate from injuries, as well as how a tissue’s mechanical adaptability might influence the progression of aging, cancer, and other health issues.
The team envisions that these findings could also shape the design of synthetic tissues and organs. For instance, when engineering artificial tissues, researchers could optimize intercellular flow within the material to enhance its performance or durability. They surmise that intercellular flow may additionally serve as a pathway for delivering nutrients or therapies, either to restore a tissue’s function or to eliminate a tumor.
“People recognize that there is abundant fluid between cells in tissues, but the significance of this, especially during tissue deformation, is often overlooked,” remarks Ming Guo, associate professor of mechanical engineering at MIT. “Now we truly demonstrate that we can observe this flow. As the tissue deforms, the movement of fluid between cells dictates the behavior. Therefore, we should focus on this aspect when studying diseases and designing tissues.”
Guo is a co-author of the new research, which includes lead author and MIT postdoctoral researcher Fan Liu PhD ’24, along with Bo Gao and Hui Li from Beijing Normal University, as well as Liran Lei and Shuainan Liu from Peking Union Medical College.
Compressed and squeezed
The tissues and organs within our bodies are perpetually undergoing mechanical alterations, ranging from the considerable strain and stretch of muscles during movement to the minor and constant contractions of the heart. In certain instances, the ease with which tissues adapt to deformation can connect to how swiftly a person recovers from, for example, an allergic reaction, a sports injury, or a cerebral stroke. However, the precise factors determining a tissue’s response to deformation remain largely elusive.
Guo and his team at MIT investigated the mechanics of tissue deformation, particularly focusing on the importance of intercellular flow, following a prior study they published in 2020. In that research, they examined tumors and analyzed how fluid can migrate from the tumor’s core to its edges, utilizing the fissures and gaps among individual tumor cells. They discovered that when a tumor undergoes compression, the intercellular flow intensifies, acting as a conveyor to transport fluid from the center outward. They concluded that this intercellular flow could facilitate tumor invasion into adjacent regions.
In their latest investigation, the team sought to determine what role this intercellular flow might play in other non-cancerous tissues.
“Whether or not fluid is permitted to flow between cells seems to significantly influence the outcome,” Guo states. “So, we opted to look beyond tumors to explore how this flow affects how other tissues respond to deformation.”
A liquid pancake
Guo, Liu, and their colleagues examined intercellular flow across various biological tissues, including cells derived from pancreatic tissue. They conducted experiments in which they first cultivated small clusters of tissue, each measuring less than a quarter of a millimeter in width and consisting of tens of thousands of individual cells. They inserted each tissue cluster into a custom-designed testing apparatus that the team specifically created for this research.
“These microtissue samples exist in a unique zone, being too large for atomic force microscopy techniques and too small for bulkier devices,” Guo explains. “Thus, we decided to develop a device.”
The researchers modified a high-precision microbalance capable of measuring minute alterations in weight. They paired this with a step motor engineered to apply pressure to a sample with nanometer accuracy. The team placed each tissue cluster on the balance individually and recorded the changing weight as it transitioned from a spherical form into a pancake shape in response to compression. Additionally, the team captured videos of the clusters during the compression process.
For each tissue type, the team created clusters of different sizes. They reasoned that if a tissue’s response is governed by intercellular flow, then larger tissues would require more time for water to permeate, thereby taking longer to relax. If the response were determined by the structure of the tissue instead of the fluid, the relaxation time should remain constant across sizes.
Over multiple experiments with various tissue types and dimensions, the team identified a consistent pattern: The larger the cluster, the lengthier the relaxation time, indicating that intercellular flow is a dominant factor in a tissue’s response to deformation.
“We demonstrate that intercellular flow is an essential element to consider for an in-depth understanding of tissue mechanics as well as potential applications in engineering living systems,” Liu states.
Looking ahead, the team plans to investigate how intercellular flow impacts brain function, especially concerning conditions such as Alzheimer’s disease.
“Intercellular or interstitial flow can aid in waste removal and nutrient delivery to the brain,” Liu adds. “Enhancing this flow in certain situations may prove beneficial.”
“As this research demonstrates, when pressure is applied to a tissue, fluid will migrate,” Guo states. “In the future, we could contemplate methods to massage a tissue to facilitate fluid transport of nutrients between cells.”
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