Multicellular migration and tissue patterning
Multicellular migration is essential to development, wound healing, and metastasis. A newly developing concept called “dynamic reciprocity” focuses upon the constant crosstalk between migrating cells and their local tissue environment. For example, cancer cells and fibroblasts are able to remodel collagen fibers in their extra-cellular matrix (ECM), while aligned fibers act as “highways” that promote efficient multicellular migration. Despite such remarkable observations, the fundamental physical understanding of multicellular migration in ECM is limited and the extent of the dynamic coupling between migrating cells and ECM is not understood.
With this in mind, we have formulated a physical theory that treats migrating cells and their environment as a multi-component active gel. This allows for an integrated study of multicellular migration and tissue patterning. Recently, we demonstrated how mechanical cell-ECM coupling can drive cellular phase separation and migration in domains. We are currently focusing on chemical aspects of dynamic reciprocity, including ECM remodeling. We aim to understand key questions in both biology and active-matter physics, such as: how does mutual cell-ECM alignment result in ECM patterns observed in vivo? What is the role of fluctuations and memory in the dynamics of active particles? We answer these questions using a combination of analytical tools from active-matter physics and numerical methods.
In the long run, a fundamental understanding of the connection between multicellular migration and ECM organization could lead to tools for the early detection of metastasis and its prevention.
- R. M. Adar and J. F. Joanny, “Permeation instabilities in active polar gels,” Phys. Rev. Lett. 127, 10 (2021).
- R. M. Adar and J. F. Joanny, “Active-gel theory for multicellular migration of polar cells in the extra-cellular matrix,” New J. Phys. 24, 073001 (2022).
Cellular volume regulation
Cellular volume regulation is an integral part of homeostasis and its physical understanding is essential for the understanding of cellular function in health and disease. Cellular volume responds to changes both in the extra-cellular osmolarity and in the properties of underlying substrates. Up to tens of minutes, volume regulation is dominated by water and ion transport through the cell membrane, referred to as “pump-leak” [4-6]. Ions diffuse passively (“leak”) through membrane-bound ion channels and are transported actively through energy-consuming pumps. The volume dynamics are determined from the water flux, driven by pressure differences across the cell membrane.
We recently developed a theory that explains cellular volume dynamics in terms of an effective ionic chemical potential, set by active pumping. Our theory explains well several recent, independent experiments where cellular volume was shown to decrease during spreading. We found that the effect is due to mechano-sensitive ion transporters that open during spreading, and allow for an ionic flux out of the cell. We are currently applying a similar framework to provide novel predictions of cellular volume regulation in response to two interesting and biologically relevant stimuli: (A) shocks, either osmotic or during immune response to pathogens; (B) stochastic tension changes during 2D migration.
- R. M. Adar and S. A. Safran, “Active volume regulation in adhered cells,” PNAS 117, 5604-5609 (2020).
- R. M. Adar, A. S. Vishen, J. F. Joanny, P. Sens, and S. A. Safran, “Volume regulation in adhered cells: roles of surface tension and cell swelling,” Biophysical J. 122, 506-512 (2023).
Concentrated ionic fluids
Electrolytes are ubiquitous in nature and industry, and can be found in each cell of our bodies, as well as the batteries of our cellular phones. While the theory of dilute electrolytes is well established, the basic physical properties of concentrated electrolytes and ionic liquids are not well understood. Namely, recent experiments imply that electrostatic interactions are surprisingly stronger in more concentrated electrolytes, while they are expected to be weaker due to screening.
The study of concentrated ionic fluids is challenging due to the combined contributions of Coulombic interactions, entropy, charge correlations, and short-range steric repulsion. In recent works, we have highlighted the role of the latter two in determining basic physical properties of concentrated ionic fluids, including their dielectric constant, screening length, charge oscillations and conductivity. However, these theories do not directly treat strong correlations beyond mean field, which are especially important in ionic liquids. In order to solve this problem, we aim to formulate a complete “strong coupling” theory of ionic fluids, using tools from quantum field theory. Such a theory is in high demand due to the growing industrial applications of these fluids in batteries and super-capacitors.
- Y. Avni, R. M. Adar, D. Andelman, and H. Orland, “Conductivity of concentrated electrolytes,” Phys. Rev. Lett. 128, 098002 (2022).
- R. M. Adar, S. A. Safran, H. Diamant, and D. Andelman, “Screening Length for Finite-size Ions in Concentrated Electrolytes,” Phys. Rev. E 100, 042615 (2019).