Current Project:How cells sense their "personal space": A role for nuclear deformations
In nature, living cells do not exist in isolation, but in the presence of chemical noise and spatial-mechanical constraints profoundly affecting cell form and function. Indeed, similar to amoebas squeezing through narrow pores in the soil in search for food, human immune cells chasing microbes maneuver through extant gaps and small constrictions in the extracellular matrix and adapt their shape and size to the confines of the local environment. This adaptability, however, is not limitless, because when cells encounter restrictive environments excessively deforming the cell body, they tend to avoid or rapidly escape such surroundings, suggesting that cells have the sense of "personal space". During the process of pathfinding in complex 3D environments, cells face multiple differently sized pores simultaneously, but often select the site of least resistance (Giordano & Lichtman. J Clin Invest, 1973; Bougherara et al. Front Immunol, 2015). How do cells make measurements of free space around them to feed their sense of "personal space"? Do they literally size up the pores in the extracellular environment? Do cells have a "ruler" allowing them to perform measurements of available extracellular space? Finally, why would cells spend energy on making measurements in environments of often poor signal to noise? Is it evolutionary advantageous? Answering these questions is the main goal of this research program.
Here, we found that cells estimate externally-imposed confinement using their largest and stiffest intracellular component, the nucleus. Cell confinement below a certain threshold compresses the nucleus and expands its envelope area. Unbuffered against area expansion due to slow turnover of constituents, the nuclear envelope becomes stretched. This in turn engages signaling via nuclear membrane stretch-sensitive proteins to the actomyosin cortex, whose vigorous contractions allow cells to minimize their surface and escape the confinement. This mechanism reveals a hitherto unappreciated non-genetic role of the nucleus in guiding cell behaviors when surrounding space becomes restrictive. The advantage of the proposed mechanism is that in contrast to the plasma membrane, nuclear membranes do not participate in constitutive membrane trafficking; their surface area thus fluctuates less. This intrinsic quiescence should privilege them to function as low-noise detectors, to readily discriminate local environmental conditions from internal traffic-induced cell area/tension fluctuations.