The LINC complex regulates Achilles tendon elastic modulus, Achilles and tail tendon collagen crimp, and Achilles and tail tendon lateral expansion during early postnatal development.

There is limited understanding of how mechanical signals regulate tendon development. The nucleus has emerged as a major regulator of cellular mechanosensation, via the linker of nucleoskeleton and cytoskeleton (LINC) protein complex. Specific roles of LINC in tenogenesis have not been explored. In this study, we investigate how LINC regulates tendon development by disabling LINC-mediated mechanosensing via dominant negative (dn) expression of the Klarsicht, ANC-1, and Syne Homology (KASH) domain, which is necessary for LINC to function. We hypothesized that LINC regulates mechanotransduction in developing tendon, and that disabling LINC would impact tendon mechanical properties and structure in a mouse model of dnKASH. We used Achilles (AT) and tail (TT) tendons as representative energy-storing and limb-positioning tendons, respectively. Mechanical testing at postnatal day 10 showed that disabling the LINC complex via dnKASH significantly impacted tendon mechanical properties and cross-sectional area, and that effects differed between ATs and TTs. Collagen crimp distance was also impacted in dnKASH tendons, and was significantly decreased in ATs, and increased in TTs. Overall, we show that disruption to the LINC complex specifically impacts tendon mechanics and collagen crimp structure, with unique responses between an energy-storing and limb-positioning tendon. This suggests that nuclear mechanotransduction through LINC plays a role in regulating tendon formation during neonatal development.

Engineering Cell-ECM-Material Interactions for Musculoskeletal Regeneration.

The extracellular microenvironment regulates many of the mechanical and biochemical cues that direct musculoskeletal development and are involved in musculoskeletal disease. The extracellular matrix (ECM) is a main component of this microenvironment. Tissue engineered approaches towards regenerating muscle, cartilage, tendon, and bone target the ECM because it supplies critical signals for regenerating musculoskeletal tissues. Engineered ECM-material scaffolds that mimic key mechanical and biochemical components of the ECM are of particular interest in musculoskeletal tissue engineering. Such materials are biocompatible, can be fabricated to have desirable mechanical and biochemical properties, and can be further chemically or genetically modified to support cell differentiation or halt degenerative disease progression. In this review, we survey how engineered approaches using natural and ECM-derived materials and scaffold systems can harness the unique characteristics of the ECM to support musculoskeletal tissue regeneration, with a focus on skeletal muscle, cartilage, tendon, and bone. We summarize the strengths of current approaches and look towards a future of materials and culture systems with engineered and highly tailored cell-ECM-material interactions to drive musculoskeletal tissue restoration. The works highlighted in this review strongly support the continued exploration of ECM and other engineered materials as tools to control cell fate and make large-scale musculoskeletal regeneration a reality.