Cells constantly encounter environments that vary in their mechanical properties, such as stiffness or softness. These mechanical conditions influence the growth, movement, and basic functions of cells, including tissue repair. Although scientists have acknowledged that cells can sense and respond to different environmental conditions, it remains unclear whether cells retain memories of their past experiences and whether these memories provide advantages in future growth.
Amit Pathak, an associate professor of mechanical engineering & materials science at Washington University in St. Louis, along with his graduate students José Almeida and Jairaj Mathur, aimed to investigate whether cells possess a memory of their previous environments. Additionally, they wanted to understand how this memory enhances the cells’ navigation through three-dimensional extracellular matrices, which are protein-rich networks surrounding cells and body tissues.
The research conducted by Almeida and Mathur revealed that cells can retain a mechanical memory of past environments. Moreover, cells can transfer this memory to the extracellular matrix that surrounds them. By doing so, cells effectively reshape their environments, sharing their acquired knowledge with future cells through the matrix, rather than individual memory. This mechanism facilitates future cell invasions by transmitting the memory externally, ensuring the preservation of collective memory beyond the lifespan of a single cell. Furthermore, this transfer of information via the matrix is much faster compared to similar adaptations that would rely on gene activation and epigenetic remodeling. The findings of this study were published in the journal Molecular Biology of the Cell on May 5.
Pathak emphasized that the question of whether cells exhibit memory-dependent behavior has been a topic of debate among biologists. Some scientists believe that cell migration is solely about adaptation to the present environment, without considering past experiences. On the other hand, some argue that cells indeed possess memory due to their complex network of genes and proteins, which would not unravel as soon as a cell leaves it.
The researchers’ work highlights the importance of both perspectives and emphasizes that there is no definitive answer, particularly in the context of cell migration. Cells can adapt to new environments, but they also retain memories. This raises the question of which aspects of cell behavior are memory-dependent and which are more reliant on adaptation.
To explore cellular memory and its role in cell migration, Almeida and Mathur combined their expertise in biomedical engineering and computational biophysics.
José Almeida conducted an experiment where cells previously exposed to stiff matrices were implanted into different 3D collagen environments. These “stiff-primed” cells exhibited higher forces compared to cells trained on soft matrices. As a result, they were able to effectively remodel the surrounding collagen fibers and facilitate invasion into new environments, regardless of the density of the fibers.
The composition of our bodies largely consists of collagen, which is a versatile material that cells can interact with and deform in various ways. Almeida highlighted the complexity of understanding how previous environments affect future ones, particularly in the context of the 3D collagen matrix. This environment allows for the examination of cross-environmental effects and provides insights into how normal cells are influenced by primed cells.
Using the experimental results and the fundamental physics of collagen deformation and cell movement, Jairaj Mathur expanded the existing model of cell migration. The updated model accounted for how cells’ mechanical memory is transferred to the matrix through collagen alignment and tension. By remodeling the matrix, cells reduce the resistance they encounter in the environment, facilitating further cell migration. The advantage gained by primed cells persists over time and is particularly advantageous in challenging environments.
Mathur explained that their model incorporates crucial aspects of how cells modify their environment, how properties from one environment enable modification of subsequent environments, and how these features are maintained across environments.
The initial focus of their investigation was on cancer. As tumors develop, the surrounding tissue becomes stiffer, and cells migrate faster in this stiff environment. However, during metastasis, tumor cells continue to migrate rapidly even in the softer, healthy tissue. This phenomenon seems counterintuitive unless the cells retain a memory of their past stiff environment.
Understanding the mechanisms of how cells store and share mechanical memories across different environments enables the team to make predictions about future cell migration. This knowledge provides valuable insights into disease progression, such as cancer metastasis and fibrosis development, as well as normal processes of development and aging. Future research plans involve further exploration of cell priming, investigating how the extracellular matrix influences cellular gene profiles, and exploring potential interventions to impede undesirable invasions, including targeted therapeutics for cancer treatment.