The LINC complex, mechanotransduction, and mesenchymal stem cell function and fate

Abstract

Mesenchymal stem cells (MSCs) show tremendous promise as a cell source for tissue engineering and regenerative medicine, and are understood to be mechanosensitive to external mechanical environments. In recent years, increasing evidence points to nuclear envelope proteins as a key player in sensing and relaying mechanical signals in MSCs to modulate cellular form, function, and differentiation. Of particular interest is the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex that includes nesprin and SUN. In this review, the way in which cells can sense external mechanical environments through an intact nuclear envelope and LINC complex proteins will be briefly described. Then, we will highlight the current body of literature on the role of the LINC complex in regulating MSC function and fate decision, without and with external mechanical loading conditions. Our review and suggested future perspective may provide a new insight into the understanding of MSC mechanobiology and related functional tissue engineering applications.

Nuclear mechanosensing controls MSC osteogenic potential through HDAC epigenetic remodeling

“…These results potentially suggest that changes in cytoplasmic morphology precede increased cytoskeletal tension via stress fiber formation, as well as changes in nuclear morphology. To understand how cytoskeletal tension could be transmitted to the nucleus, we next looked at Lamin A levels, as Lamin A has been known to play a key role in force transmission through cytoplasm to the nucleus via the LINC complex (7,26). We characterized Lamin A intensity over time after stiffening.…”

“…Cells convey these physical signals to their internal chemical machinery via mechanotransduction pathways, which can regulate key cellular behavior such as proliferation and differentiation ( 2 – 6 ). Apart from biochemical signaling, recent studies demonstrate that the nucleus can act as a direct mechanosensor by undergoing deformation in the presence of mechanical forces, leading to changes in the nuclear envelope structure and composition ( 7 – 9 ). This structural deformation can subsequently alter chromatin organization, epigenetic modifications, and gene expression ( 10 – 12 ).…”

Crucial Role of Lamin A/C in the Migration and Differentiation of MSCs in Bone

“…In fact, mutations in lamin A/C disturb nuclear-cytoskeletal coupling in LMNA -/- mice [ 66 ]. The nucleus is mechanically connected to the rest of the cell, via Linker of Nucleus and Cytoskeleton (LINC) complex structures which are located in the nuclear envelope [ 67 , 68 ]. This complex consists of SUN (Sad1 and UNC-84) proteins anchored in the inner nuclear membrane and nuclear envelope spectrin-repeat-containing proteins (nesprins) anchored in the outer nuclear membrane ( Figure 1 ).…”

“…This complex consists of SUN (Sad1 and UNC-84) proteins anchored in the inner nuclear membrane and nuclear envelope spectrin-repeat-containing proteins (nesprins) anchored in the outer nuclear membrane ( Figure 1 ). In that way, the LINC complex connects the cytoplasmic cytoskeleton with the inner nucleoskeletal lamin A/C network [ 68 , 69 ], allowing the reorganization of lamins in response to mechanical stress [ 70 ]. Therefore, it is responsible for limiting nuclear deformation [ 67 ].…”

Emerging roles of cytoskeletal proteins in regulating gene expression and genome organization during differentiation

“…Another interesting perspective is that the actin cytoskeleton is linked with the nuclear lamina via the LINC complex, which serves as a sensing machinery to mechanical signals [36,37]. Since the nuclear lamina plays a central role in chromatin organization by forming the anchor of Lamina-Associated Domains (LADs) [38], dynamic changes of the actin cytoskeleton upon mechanical stress can potentially affect chromatin organization.…”