Glycosaminoglycans Modulate Long-Range Mechanical Communication Between Cells in Collagen Networks

Abstract

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.

Injury and a program of fetal wound healing in the fetal and neonatal extrahepatic bile duct

“…Given that that HA can disrupt collagen organization [18], we asked whether there were organizational differences between the collagen in EHBD remnants from BA patients and controls. The structure of the collagen around the HA layers in BA remnants was determined using the ImageJ plugin TWOMBLI to identify matrix patterns.…”

Versican binds collagen via its G3 domain and regulates the organization and mechanics of collagenous matrices

“…Type I collagen, the most abundant protein in the body, forms a dynamic fibrous network that plays a critical role in maintaining normal cell and tissue structure, function, and mechanics. The structure and mechanics of the collagen fibrous network are interrelated [1] and are highly regulated by factors including cell-generated force [2] and other extracellular matrix (ECM) components such as fibronectin [3], glycosaminoglycans (GAGs), and proteoglycans (proteins modified by GAGs) [4][5][6]. GAGs are highly negatively charged and contribute to collagen mechanics by attracting water, thereby swelling and resisting compression [7].…”