Deciphering the mechanisms of red blood cells filtration through the submicronic slits of the spleen
Although their apparent simple morphology, red blood cells (RBCs) are very deformable with well-adjusted rheological properties enabling their fast, efficient and resilient transport into the blood stream. In the spleen, RBCs pass the most stringent physical fitness test of the blood circulation, consisting in squeezing through submicronic slits where they undergo extreme deformations. This test which is believed to filter RBCs by retaining the stiff ones is known to play an important role in many diseases such as malaria or sickle cell disease. However, the mechanisms that govern the cell dynamics through the slits are still unknown. CINAM has developed microfluidic chips with slits of physiological dimensions where RBCs are observed when crossing the slits. The mathematical laboratory I2M is specialist in complex fluid modeling, fluid mechanics, and collective motion. We will combine our expertise to decipher, both from experiments and mathematical modeling, the role of RBC rheological properties (complex fluid-structure interactions) and active processes on their ability to cross the spleen filter. In particular, we will investigate the activation of the mechano-sensitive ionic channel PIEZO1 and its interaction with the Gardos channel resulting in a possible reduction of the RBC volume.
Microcirculation, red blood cells, mechano-transduction, mathematical modeling, fluid structure interaction
The objective is to highlight the rheological and active mechanisms that allow efficient RBC transport in the blood stream. Based on a quantitative set of data that we will acquire using microdevices designed in the lab, the aim is to build mathematical models to understand the relationships between the RBC dynamics through submicronic slits, their mechanical properties and active processes. Our goal is to elucidate how an external mechanical constraint, triggering activations of ionic channels, leads to a reduction of RBC volume.
Proposed approach (experimental / theoretical / computational)
Experimentally we will design several microfluidic devices containing slits with submicron width replicating the physiological dimensions of slits in the spleen . RBC dynamics will be observed through the slits and recorded by optical microscopy. We will establish quantitative relationships between physical parameters (such as cell deformation, transit time, retention rate, relaxation time of RBC shapes) and the slit geometry, the applied pressure, and the activity of the ion channels. This activity will be regulated by commercial activators and inhibitors of PIEZO1 and Gardos and by calcium concentration.
Conjointly, we will develop a theoretical framework for thinking about these issues. This framework will be built around models of fluid-structure interaction to understand the mechanisms and dynamics of red blood cell deformation. A crucial mathematical issue is the dynamics and regularity of the free boundary corresponding to the cell membrane, this question is all the more difficult inasmuch as cell volume changes have to be taken into account.
The project raises important questions in physiology concerning the mechanisms of circulation in the spleen and in biology concerning how mechanics affects cell dynamics and involves mechano-transduction and ionic channels.
It challenges instrumental physics to develop nano-microfluidic devices for the observation of red blood cells, which requires cutting-edge technology.
It challenges mathematics to build, analyse and validate complex systems of coupled nonlinear equations modelling fluid-(elastic)structure interactions in very complex geometries from a theoretical and numerical standpoint.
This project proposes a combination of know-how, expertise and knowledge from different scientific fields and cultures. Physics and biology experiments will be carried out by the biophysicists in CINAM, and theoretical approaches will be proposed by mathematicians at I2M.
The expected student will have a solid background in physics and an interest in applied mathematics. He/she will be interested by both experiments and mathematical modelling. He/she should have a strong attraction for questions of biology and a real desire to get closer to biologists, to discuss with them and learn to manipulate biological matter and the complexity of the living world.