Macro- to Microscale Strain Transfer in Fibrous Tissues is Heterogeneous and Tissue-Specific

Abstract

Mechanical deformation applied at the joint or tissue level is transmitted through the macroscale extracellular matrix to the microscale local matrix, where it is transduced to cells within these tissues and modulates tissue growth, maintenance, and repair. The objective of this study was to investigate how applied tissue strain is transferred through the local matrix to the cell and nucleus in meniscus, tendon, and the annulus fibrosus, as well as in stem cell-seeded scaffolds engineered to reproduce the organized microstructure of these native tissues. To carry out this study, we developed a custom confocal microscope-mounted tensile testing device and simultaneously monitored strain across multiple length scales. Results showed that mean strain was heterogeneous and significantly attenuated, but coordinated, at the local matrix level in native tissues (35-70% strain attenuation). Conversely, freshly seeded scaffolds exhibited very direct and uniform strain transfer from the tissue to the local matrix level (15-25% strain attenuation). In addition, strain transfer from local matrix to cells and nuclei was dependent on fiber orientation and tissue type. Histological analysis suggested that different domains exist within these fibrous tissues, with most of the tissue being fibrous, characterized by an aligned collagen structure and elongated cells, and other regions being proteoglycan (PG)-rich, characterized by a dense accumulation of PGs and rounder cells. In meniscus, the observed heterogeneity in strain transfer correlated strongly with cellular morphology, where rounder cells located in PG-rich microdomains were shielded from deformation, while elongated cells in fibrous microdomains deformed readily. Collectively, these findings suggest that different tissues utilize distinct strain-attenuating mechanisms according to their unique structure and cellular phenotype, and these differences likely alter the local biologic response of such tissues and constructs in response to mechanical perturbation.

Cytoskeletal to Nuclear Strain Transfer Regulates YAP Signaling in Mesenchymal Stem Cells

“…Fiber-reinforced soft tissues are exposed to large loads and deformations that are transmitted through their hierarchical extracellular matrix to both cells and their nuclei within (20), regulating numerous cellular processes and playing important roles in the formation, maintenance, and ultimately degeneration of these tissues. In the context of engineered replacements, it will be important to understand both the extent to which these macro-to-microscale deformations are recapitulated in the engineered constructs and the mechanoresponsiveness of the cell types used in the fabrication of these constructs.…”

“…MSCs are widely used in these types of applications (4), and it is well established that they respond to mechanical signals in a manner that is dependent on a contractile cytoskeleton (1,2). As with native tissue cells, nuclei within MSCs also undergo marked deformations with applied tensile stretch (20,23,24). In this study, we found that the presence of a patent actin cytoskeleton, the tension within this cytoskeletal network, and the connections it makes to the nucleus through nesprin 1 giant, regulate the transmission of strain to the nucleus.…”

“…In native tissues, nuclear strain transmission is variable, depending on tissue type and local matrix properties (20)(21)(22). In three-dimensional aligned fibrous environments, nuclear strain transfer depends on a patent actin cytoskeleton, but is independent of microtubules and intermediate filaments (23).…”

Novel image analysis methods for quantification of in situ 3-D tendon cell and matrix strain

“…This 3-D approach is unique because it considers out-ofplane motion, which can occur from misalignment with the uniaxial loading direction or anisotropy. 2-D methods have been used extensively to quantify strain transfer from the macro to microscales (Han et al, 2013; Upton et al, 2008), but many studies acknowledge that results are confounded by artifacts from excluding the effect of strain in the third dimension. Our matrix strain and cell deformation methods capture the 3-D microstructural response and how cells reorient or deform multi-dimensionally, providing a comprehensive picture of the strain environment.…”

Evolution of network architecture in a granular material under compression

“…Finally, the ability to identify and quantify mesoscale architecture is important in other physical systems more broadly. The brain [56,62,[72][73][74] and biomaterials [75][76][77][78][79] are a few examples of systems where intermediate structure is crucial to function.…”