Collagen Assembly at the Cell Surface: Dogmas Revisited

Abstract

With the increased awareness about the importance of the composition, organization, and stiffness of the extracellular matrix (ECM) for tissue homeostasis, there is a renewed need to understand the details of how cells recognize, assemble and remodel the ECM during dynamic tissue reorganization events. Fibronectin (FN) and fibrillar collagens are major proteins in the ECM of interstitial matrices. Whereas FN is abundant in cell culture studies, it is often only transiently expressed in the acute phase of wound healing and tissue regeneration, by contrast fibrillar collagens form a persistent robust scaffold in healing and regenerating tissues. Historically fibrillar collagens in interstitial matrices were seen merely as structural building blocks. Cell anchorage to the collagen matrix was thought to be indirect and occurring via proteins like FN and cell surface-mediated collagen fibrillogenesis was believed to require a FN matrix. The isolation of four collagen-binding integrins have challenged this dogma, and we now know that cells anchor directly to monomeric forms of fibrillar collagens via the α1β1, α2β1, α10β1 and α11β1 integrins. The binding of these integrins to the mature fibrous collagen matrices is more controversial and depends on availability of integrin-binding sites. With increased awareness about the importance of characterizing the total integrin repertoire on cells, including the integrin collagen receptors, the idea of an absolute dependence on FN for cell-mediated collagen fibrillogenesis needs to be re-evaluated. We will summarize data suggesting that collagen-binding integrins in vitro and in vivo are perfectly well suited for nucleating and supporting collagen fibrillogenesis, independent of FN.

Keywords: collagen fibrillogenesis; fibronectin; integrin; integrin α11; integrin α2; integrin α5.

Figure 1

Collagen and fibronectin fibrillogenesis. (A) Fibronectin fibrillogenesis. Binding of fibronectin (FN) to the FN receptor α5β1 integrin leads to a conformational change in FN exposing sites needed for fibril formation. The actin cytoskeleton exerts a pulling force on α5β1 integrins to unfold FN. (B) Indirect mode of collagen assembly (fibronectin-dependent). Fibrillar collagens are secreted as pro-collagen. FN facilitates collagen assembly by concentrating BMP-1, which is involved in collagen pro-peptide cleavage. Collagen could then interact with FN matrix that serves as nucleator of collagen assembly. (C) Direct mode of collagen assembly (collagen-binding, integrin-dependent). The collagen-binding integrins α2β1 and α11β1 directly interact with collagen. They have been suggested to assist in collagen assembly. The FN and collagen matrix assembly are closely linked. These integrins might have a central role in the conditions where FN assembly is dependent on collagen fibrillogenesis.

Figure 2

Collagen Ⅴ in collagen I-containing fibrils. Collagen Ⅴ is a minor fibrillar collagen composed of a triple helical part and a N-terminal domain, which is only partially processed, formed by a globular domain and the col2 domain, which is a short triple helix. Collagen Ⅴ (pink) plays a role in nucleating assembly of collagen Ⅰ (blue) matrix, which may also contain collagen Ⅲ (green). Fibrillar collagens are assembled into microfibrils that aggregate to form fibrils and then fibers. Collagen Ⅴ triple helix is hidden in the interior of the fibril with the N-terminal domain protruding at the fibril surface. Collagen-binding integrins at the cell surface may potentially interact with the short triple helix present in the N-terminal domain of the collagen Ⅴ during the formation of fibrils.