Deciphering Nuclear Mechanobiology in Laminopathy

Abstract

Extracellular mechanical stimuli are translated into biochemical signals inside the cell via mechanotransduction. The nucleus plays a critical role in mechanoregulation, which encompasses mechanosensing and mechanotransduction. The nuclear lamina underlying the inner nuclear membrane not only maintains the structural integrity, but also connects the cytoskeleton to the nuclear envelope. Lamin mutations, therefore, dysregulate the nuclear response, resulting in abnormal mechanoregulations, and ultimately, disease progression. Impaired mechanoregulations even induce malfunction in nuclear positioning, cell migration, mechanosensation, as well as differentiation. To know how to overcome laminopathies, we need to understand the mechanisms of laminopathies in a mechanobiological way. Recently, emerging studies have demonstrated the varying defects from lamin mutation in cellular homeostasis within mechanical surroundings. Therefore, this review summarizes recent findings highlighting the role of lamins, the architecture of nuclear lamina, and their disease relevance in the context of nuclear mechanobiology. We will also provide an overview of the differentiation of cellular mechanics in laminopathy.

Keywords: cytoskeleton; lamin; laminopathy; nucleus.

Figure 1

Nuclei of a normal cell and progeria cell. Left: The nuclear lamina is composed of lamin A and C (lamin A/C). Lamin A/C processing consists of multiple steps: (i) The farnesyl group is added to pre-lamin A/C by FTase; and (ii) cleavage by the zinc metalloproteinase Ste24 homologue (ZMPSTE24) finalizes the maturation. Heterochromatin is bound to the nuclear envelope by interactions with HP1 and LBR. Right: The nucleus of the progeria cell does not have heterochromatins bound to the nuclear envelope. Cleavage by the zinc metalloproteinase Ste24 homologue (ZMPSTE24) is not involved in the process of progerin production. Progerin accumulation in the nuclear lamina contributes to the lamina thickening.

Figure 2

Nuclear positioning in laminopathic cell migration. Left: Normal cells are polarized in the order of “front-end nucleus– microtubule-organizing center (MTOC) rear end”. Black arrows indicate the direction of nuclear migration. Blue arrow shows the direction of cell migration. Right: Laminopathic cells have a deformed nucleus and weak connection between the nucleus and cytoskeleton. Since F-actin formation is disturbed in laminopathic cells, laminopathic cells lose their directionality in cell migration.

Figure 3

Mechanosensation and differentiation determined by lamin and the substrate stiffness. Cells on hydrogels of different stiffnesses show distinct mechanosensation. Substrate stiffness-dependent stem cell differentiation depends on different lamin A/C expression. (a) A cell on the compliant substrate is less spread out, and cytoskeleton formation and nuclear shape maintenance are inhibited by the compliant substrate. On the compliant substrate, lamin A/C expression decreases and the stem cell can differentiate into an adipocyte. (b) A normal cell on the rigid substrate is fully spread out with well-organized F-actin and microtubules. Focal adhesions on the rigid substrate are also bigger than on the soft substrate. Lamin A/C expression increases as the substrate stiffness increases. Therefore, stem cells with a rigid nucleus can differentiate into osteoblasts and myocytes. (c) Laminopathic cells featuring fragile nuclei show miniscule focal adhesions, even when laminopathic cells are on the rigid substrate. Laminopathic cells display attenuated mechanotransduction due to weak nucleus–cytoskeletal connections.