Distinct effects of different matrix proteoglycans on collagen fibrillogenesis and cell-mediated collagen reorganization

Abstract

The extracellular matrix (ECM) is a complex mixture composed of fibrillar collagens as well as additional protein and carbohydrate components. Proteoglycans (PGs) contribute to the heterogeneity of the ECM and play an important role in its structure and function. While the small leucine rich proteoglycans (SLRPs), including decorin and lumican, have been studied extensively as mediators of collagen fibrillogenesis and organization, the function of large matrix PGs in collagen matrices is less well known. In this study, we showed that different matrix PGs have distinct roles in regulating collagen behaviors. We found that versican, a large chondroitin sulfate PG, promotes collagen fibrillogenesis in a turbidity assay and upregulates cell-mediated collagen compaction and reorganization, whereas aggrecan, a structurally-similar large PG, has different and often opposing effects on collagen. Compared to versican, decorin and lumican also have distinct functions in regulating collagen behaviors. The different ways in which matrix PGs interact with collagen have important implications for understanding the role of the ECM in diseases such as fibrosis and cancer, and suggest that matrix PGs are potential therapeutic targets.HighlightsSmall leucine rich proteoglycans (SLRPs) and large chondroitin sulfate (CS) proteoglycans (PGs) have distinct effects on collagen fibrous network behavior.Unlike other matrix proteoglycans, versican promotes collagen fibrillogenesis in an in vitro spectrophotometric (turbidity) assay.The versican core protein has a larger impact on collagen behavior in a fibrillogenesis assay than its glycosaminoglycan chains do.Versican increases the diameter of collagen fibers and the porosity of collagen fibrous networks, unlike aggrecan and SLRPs.The addition of versican to collagen does not alter fibroblast contractility but leads to enhanced cell-mediated collagen reorganization and contraction.

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

“…However, in native ECM, the content of free GAGs and PG-bound GAGs is still unclear. As different PGs appear to interact differently with collagen 29 , PG-bound GAGs (fixed charge residues) might have complicated effects on mechanical communication between cells. Thus, there is a particular need to investigate and compare the regulation of free versus PG-bound GAGs on fibrous network as one future direction for modeling force transmission in native ECM.…”

“…All the samples were sealed with parafilm and kept in PBS at 4°C. Second-harmonic generation (SHG) imaging was used to visualize collagen fibers 29 .…”

Inhibition of glucose use improves structural recovery of injured Achilles tendon in mice

“…Previous in vitro studies have demonstrated that the high‐molecular‐weight of chondroitin sulfate retards the rate of collagen fibril formation by monitoring gelation rate 50 . In contrast, recent studies have shown that versican, but not aggrecan, promotes collagen fibrillogenesis in a turbidity assay, and chondroitin sulfate gives a minor supportive effect on this stimulation 6 . These in vitro studies suggest a complexity of interaction between collagen fibrils and specific proteoglycan core proteins and GAGs in the regulation of collagen fibril formation.…”

“…Proteoglycans such as aggrecan and versican, with sulfated glycosaminoglycan (GAG) chains can form big aggregates, retain water, and provide the ability to resist compressive and tensile force to the tendon 2,3 . Proteoglycans may also affect collagen fibrllogenesis 6,7 . Thus both collagen fibers and proteoglycans are important modulators of mechanical properties of tendons.…”

Programmable and Contractile Materials Through Cell Encapsulation in Fibrous Hydrogel Assemblies

“…This bottom-up approach relies on stromal cell ECM contraction and physical interactions with the matrix to form high cell density tissue mimics (3,45). Although we have learned a great deal from current microtissue systems, there is a need for systems where the matrix can be tuned to better understand the contribution of ECM properties to tissue morphogenesis (45) and ECM-based diseases such as fibrosis (46). Currently, most commercially available ECM systems (e.g., type I collagen, fibrin, Matrigel) have limited control over biochemical and biophysical properties and would benefit from synthetic versions where such properties can be modulated.…”