PT  - JOURNAL ARTICLE
AU  - Chen, Xingyu
AU  - Chen, Dongning
AU  - Ban, Ehsan
AU  - Janmey, Paul A.
AU  - Wells, Rebecca G.
AU  - Shenoy, Vivek B.
TI  - Glycosaminoglycans Modulate Long-Range Mechanical Communication Between Cells in Collagen Networks
AID  - 10.1101/2021.09.13.460122
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.09.13.460122
4099  - http://biorxiv.org/content/early/2021/09/14/2021.09.13.460122.short
4100  - http://biorxiv.org/content/early/2021/09/14/2021.09.13.460122.full
AB  - Cells can sense and respond to mechanical forces in fibrous extracellular matrices (ECM) over distances much greater than their size. This phenomenon, termed long-range force transmission, is enabled by the realignment (buckling) of collagen fibers along directions where the forces are tensile (compressive). However, whether other key structural components of the ECM, in particular glycosaminoglycans (GAGs), can affect the efficiency of cellular force transmission remains unclear. Here we developed a theoretical model of force transmission in collagen networks with interpenetrating GAGs, capturing the competition between tension-driven collagen-fiber alignment and the swelling pressure induced by GAGs. Using this model, we show that the swelling pressure provided by GAGs increases the stiffness of the collagen network by stretching the fibers in an isotropic manner. We found that the GAG-induced swelling pressure can help collagen fibers resist buckling as the cells exert contractile forces. This mechanism impedes the alignment of collagen fibers and decreases long-range cellular mechanical communication. We experimentally validated the theoretical predictions by comparing collagen fiber alignment between cellular spheroids cultured on collagen gels versus collagen-GAG co-gels. We found significantly less alignment of collagen in collagen-GAG co-gels, consistent with the prediction that GAGs can prevent collagen fiber alignment. The roles of GAGs in modulating force transmission uncovered in this work can be extended to understand pathological processes such as the formation of fibrotic scars and cancer metastasis, where cells communicate in the presence of abnormally high concentrations of GAGs.Statement of significance Glycosaminoglycans (GAGs) are carbohydrates that are expressed ubiquitously in the human body and are among the key macromolecules that influence development, homeostasis, and pathology of native tissues. Abnormal accumulation of GAGs has been observed in metabolic disorders, solid tumors, and fibrotic tissues. Here we theoretically and experimentally show that tissue swelling caused by the highly polar nature of GAGs significantly affects the mechanical interactions between resident cells by altering the organization and alignment of the collagenous extracellular matrix. The roles of GAGs in modulating cellular force transmission revealed here can guide the design of biomaterial scaffolds in regenerative medicine and provides insights on the role of cell-cell communication in tumor progression and fibrosis.Competing Interest StatementThe authors have declared no competing interest.