The Mechanics of Neutrophils: Synthetic Modeling of Three Experiments

Abstract

Much experimental data exist on the mechanical properties of neutrophils, but so far, they have mostly been approached within the framework of liquid droplet models. This has two main drawbacks: 1), It treats the cytoplasm as a single phase when in reality, it is a composite of cytosol and cytoskeleton; and 2), It does not address the problem of active neutrophil deformation and force generation. To fill these lacunae, we develop here a comprehensive continuum-mechanical paradigm of the neutrophil that includes proper treatment of the membrane, cytosol, and cytoskeleton components. We further introduce two models of active force production: a cytoskeletal swelling force and a polymerization force. Armed with these tools, we present computer simulations of three classic experiments: the passive aspiration of a neutrophil into a micropipette, the active extension of a pseudopod by a neutrophil exposed to a local stimulus, and the crawling of a neutrophil inside a micropipette toward a chemoattractant against a varying counterpressure. Principal results include: 1), Membrane cortical tension is a global property of the neutrophil that is affected by local area-increasing shape changes. We argue that there exists an area dilation viscosity caused by the work of unfurling membrane-storing wrinkles and that this viscosity is responsible for much of the regulation of neutrophil deformation. 2), If there is no swelling force of the cytoskeleton, then it must be endowed with a strong cohesive elasticity to prevent phase separation from the cytosol during vigorous suction into a capillary tube. 3), We find that both swelling and polymerization force models are able to provide a unifying fit to the experimental data for the three experiments. However, force production required in the polymerization model is beyond what is expected from a simple short-range Brownian ratchet model. 4), It appears that, in the crawling of neutrophils or other amoeboid cells inside a micropipette, measurement of velocity versus counterpressure curves could provide a determination of whether cytoskeleton-to-cytoskeleton interactions (such as swelling) or cytoskeleton-to-membrane interactions (such as polymerization force) are predominantly responsible for active protrusion.

Cell mechanics and mechanotransduction: pathways, probes, and physiology

“…In addition, the presence of the nucleus affects neutrophil aspiration, especially under large deformations (46). The internal velocity field and changes in geometric parameters experienced by neutrophils during various deformation have been modeled using finite-element analysis, showing among other things a weakness in the classic Brownian ratchet model to explain the magnitude of force generation (39).…”

Implications of a poroelastic cytoplasm for the dynamics of animal cell shape

“…This formalism accounts for the dynamics of cytoplasm by including the movement of liquid through a soft porous mesh. It has been previously applied in various forms to understand aspects of the mechanics of whole cells [9,10], and extracellular matrix gels such as collagen [11], and cartilage [12,13]. Here, we review its implications for motility of single cells that involves shape change, such as leading edge protrusion or cleavage furrow invagination.…”

On a poroviscoelastic model for cell crawling

“…It was first considered for modelling cell motility by Dembo et al (1984) and since developed by e.g. Dembo and Harlow (1986); Alt and Dembo (1999); Herant et al (2003); Oliver et al (2005); Rubinstein et al (2005); Zajac et al (2008); Kuusela and Alt (2009);Cogan and Guy (2010) and Kimpton et al (2012). The key advantages of this framework over those discussed above are its ability to: describe polymerization and depolymerization with actin monomers moving out of and into the aqueous cytosol; capture drag between the phases and swelling of the network.…”