Physical plasticity of the nucleus in stem cell differentiation

Abstract

Cell differentiation in embryogenesis involves extensive changes in gene expression structural reorganization within the nucleus, including chromatin condensation and nucleoprotein immobilization. We hypothesized that nuclei in naive stem cells would therefore prove to be physically plastic and also more pliable than nuclei in differentiated cells. Micromanipulation methods indeed show that nuclei in human embryonic stem cells are highly deformable and stiffen 6-fold through terminal differentiation, and that nuclei in human adult stem cells possess an intermediate stiffness and deform irreversibly. Because the nucleo-skeletal component Lamin A/C is not expressed in either type of stem cell, we knocked down Lamin A/C in human epithelial cells and measured a deformability similar to that of adult hematopoietic stem cells. Rheologically, lamin-deficient states prove to be the most fluidlike, especially within the first Ϸ10 sec of deformation. Nuclear distortions that persist longer than this are irreversible, and fluorescence-imaged microdeformation with photobleaching confirms that chromatin indeed flows, distends, and reorganizes while the lamina stretches. The rheological character of the nucleus is thus set largely by nucleoplasm/chromatin, whereas the extent of deformation is modulated by the lamina. chromatin remodeling ͉ cell mechanics ͉ nuclear plasticity

A Chemomechanical Model for Nuclear Morphology and Stresses during Cell Transendothelial Migration

“…1 c; refer to the Supporting Material for details). Recent work has shown that the nucleus is also viscoelastic, but the timescale of viscous relaxation is of the order of 1-300 s (14,15,19,20), which is an order of magnitude smaller than the time it takes the nucleus to pass through endothelial gaps/constrictions (3). Thus, the elastic properties we use here are the moduli after the viscous effects have relaxed.…”

“…Previously, Pajerowski et al reported that cell nuclei experience irreversible deformation after release of pressure applied by a micropipette (15). A later study showed evidence that dynamic loading of the nucleus can lead to permanent structural changes in chromatin (40).…”

“…In light of experimental discoveries that identified nuclear morphological changes and their implications for cellular behavior, progress has been made in quantifying mechanical and rheological properties of the nucleus (14,15). Yet how actomyosin-generated forces coordinate with geometric and mechanical parameters (such as the constriction size and the stiffness of the extracellular matrix and the nucleus) to modulate the nuclear morphology during cell passage through small openings remains poorly understood.…”

Cellular contractility and substrate elasticity: a numerical investigation of the actin cytoskeleton and cell adhesion

“…Significant differences have been reported in nuclear stresses and apparent stiffness levels between stem cells and differentiated phenotypes (Pajerowski et al 2007). Furthermore, it is well established that substrate stiffness directs stem cell linage (Discher et al 2005).…”

La réponse inhabituelle des noyaux de cellules souches embryonnaires aux forces mécaniques

“…Pourquoi la machinerie génétique de la cellule [7] serait-elle couplée aux forces du monde extracellulaire ? Cette question se pose encore plus dans le cas des cellules souches embryonnaires (CSE), qui n'expriment pas les lamines A et C [8], responsables de l'intégrité mécanique du noyau [9]. Si la cellule était simplement contrainte de suivre un programme génétique régulé par des signaux moléculaires, pourquoi la forme du noyau serait-elle influencée par le cytosquelette ?…”