Nuclear envelope mechanobiology: linking the nuclear structure and function

Abstract

The nucleus, central to cellular activity, relies on both direct mechanical input as well as its molecular transducers to sense external stimuli and respond by regulating intra-nuclear chromatin organization that determines cell function and fate. In mesenchymal stem cells of musculoskeletal tissues, changes in nuclear structures are emerging as a key modulator of their differentiation and proliferation programs. In this review we will first introduce the structural elements of the nucleoskeleton and discuss the current literature on how nuclear structure and signaling are altered in relation to environmental and tissue level mechanical cues. We will focus on state-ofthe-art techniques to apply mechanical force and methods to measure nuclear mechanics in conjunction with DNA, RNA, and protein visualization in living cells. Ultimately, combining realtime nuclear deformations and chromatin dynamics can be a powerful tool to study mechanisms of how forces affect the dynamics of genome function.

Depletion of Sun1/2 induces heterochromatin accrual in mesenchymal stem cells during adipogenesis

“…During development and in mechanically active tissues such as bone and muscle, progenitor cell differentiation is highly dependent upon a cell’s ability to sense extracellular mechanical cues and transmit this information into nucleus and alter chromatin structure. Therefore, disrupting Nesprin-Sun binding of the LINC complex via expression of a dominant-negative KASH (dnKASH) and depletion of either Sun or Nesprin proteins have been used interchangeably to study the effects of nucleo-cytoskeletal connectivity on cell function and differentiation 17 . Indeed, both dnKASH overexpression and Nesprin/Sun depletion approaches have been shown to affect progenitor cell differentiation.…”

Appetizer on soft matter physics concepts in mechanobiology

“…On the other hand, the active responses of the biological entities manifest themselves in changing microscopic conformations by synthesis or degradation of the components or remodeling their microstructures, which could be captured by spatial information profiles. Some active changes of bioentities such as dynamics of molecular motors (Veigel & Schmidt, 2011), folding/unfolding of proteins (Petrosyan et al, 2021), sol–gel transition of nuclear chromatins (Eshghi et al, 2021; Khanna et al, 2019), opening the ion channels on the nuclear envelopes (Goelzer et al, 2021; Matsuda & Mofrad, 2022), the alignment of filament bundles in the cytoskeleton (Scheff et al, 2021), or the secretion of components like collagens to extracellular matrix (ECM) (Chaudhuri et al, 2020; Humphrey et al, 2014; Vogel, 2018) have triggered a boom of interest in the mechanobiology field.…”

The Nuclear Envelope as a Regulator of Immune Cell Function

“…A complete map of the cellular pathways activated by mechanosensing in immune cells is yet to be fully elucidated but appears to involve plasma membrane ion channels such as PIEZO1 (123) and TRPV4 (124), adhesion molecules and cytoskeleton rearrangement, and the reader is pointed towards several recent reviews on the subject (125)(126)(127). The NE and its associated proteins are also involved in the signal transduction mechanisms activated by changes in mechanical forces through interactions between the cytoskeleton, LINC protein complexes and the lamin network which attaches the INM to laminassociated-domains (LADs) within chromatin and thus influences chromatin dynamics (128,129). Along with evidence that the NE represents a core component of mechanical signal transduction, a number of seminal studies have now also demonstrated that the NE itself is a sensor of mechanical forces (130)(131)(132), a function it may be well suited for (133).…”