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

Abstract

Type I collagen is the most abundant structural protein in the body and, with other fibrillar collagens, forms the fibrous network of the extracellular matrix (ECM). Another group of ECM polymers, the glycosaminoglycans (GAGs) and GAG-modified proteoglycans, play important roles in regulating collagen behaviors and contribute to the compositional, structural and mechanical complexity of the ECM. While the binding between collagen and small leucine-rich proteoglycans (SLRPs) has been studied in detail, the interactions between collagen and the large bottlebrush proteoglycan versican are not well understood. Here, we report that versican binds collagen directly and regulates collagen structure and mechanics. Versican colocalizes with collagen fibers in vivo and binds to collagen via its C-terminal G3 domain (a non-GAG-modified domain present in all known versican isoforms) in vitro; it promotes the deposition of a highly-aligned collagen-rich matrix by fibroblasts. Versican also shows an unexpected effect on the rheology of collagen gels in vitro, causing decreased stiffness and attenuated shear strain stiffening, and the cleavage of versican in liver results in reduced tissue compression stiffening. Thus, versican is an important collagen binding partner, playing a role in modulating collagen organization and mechanics.

Glisson’s capsule matrix structure and function is altered in patients with cirrhosis irrespective of aetiology

“… 38 , 39 It is a likely contributor to the change in the collagen network organisation observed within the capsule, given that it is known to bind collagen fibres directly and to drive collagen bundle organisation. 38 , 40 Versican can also induce a profibrotic phenotype in capsular fibroblasts and adjacent hepatic stellate cells. 39 , 41 …”

Glisson’s capsule structure and function is altered in cirrhotic patients irrespective of etiology

“…Versican, an HA-binding proteoglycan found primarily in the cirrhotic capsule, is also involved in collagen fibrillogenesis, cell adhesion and migration, and signaling (41, 42). It is a likely contributor to the change in the collagen network organization observed within the capsule, given that it is known to bind collagen fibers directly and to drive collagen bundle organization (41, 43). Versican may also induce a pro-fibrotic phenotype in capsular fibroblasts and adjacent hepatic stellate cells (42, 44).…”