Physical plasticity of the nucleus in stem cell differentiation

TLDR

Cell differentiation in embryogenesis involves extensive nuclear reorganization, including chromatin condensation and nucleoprotein immobilization. The authors hypothesized that naive stem cell nuclei would be physically plastic and more pliable than differentiated nuclei. Knocking down the nucleo‑skeletal component Lamin A/C in human epithelial cells produced deformability comparable to adult hematopoietic stem cells, indicating Lamin A/C’s role in nuclear mechanics. Micromanipulation shows embryonic stem cell nuclei are highly deformable and stiffen six‑fold upon differentiation, adult stem cell nuclei are intermediate and deform irreversibly, lamin‑deficient cells are most fluid‑like for the first ~10 s, and chromatin flow with lamina stretching underlies irreversible distortions, revealing that nucleoplasm/chromatin largely set rheology while the lamina modulates deformation extent.

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 fluid-like, especially within the first approximately 10 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.