Everything you need to know about fibronectin.

Fibronectin is, above all, an architectural protein of the dermal extracellular matrix.

This is a high-molecular-weight glycoprotein (≈ 500–600 kDa in its dimeric form). It is one of the structural components of the extracellular matrix and has a remarkable capacity for interaction: it binds to integrins, the transmembrane receptors on the cell surface, but also to other matrix proteins, such as the collagen, and elastin or even fibrin. This binding versatility confers it a role as a anchoring and integration platform for mechanical and biochemical signals. By linking cells to their extracellular environment, fibronectin participates in cell adhesion, migration, proliferation and differentiation. It thus plays a central role in various biological processes, such as the wound healing or embryonic development.

In vertebrates, one can distinguish two principal forms of fibronectin, derived from the same gene but differentiated by alternative splicing mechanisms of pre-mRNA.

• The plasma fibronectin, soluble, is synthesised by hepatocytes and circulates in the blood plasma at an average concentration of about 300 µg/mL. It is particularly involved in haemostasis and early tissue repair by binding to fibrin at sites of injury.

• The cellular fibronectin, insoluble, constitutes a major component of the extracellular matrix. It is secreted mainly by fibroblasts, but also by other cells such as keratinocytes or endothelial cells in a soluble form, and then assembled into an insoluble fibrillar network at the cell surface through an integrin-dependent process.

Structurally, fibronectin consists of two nearly identical polypeptide chains, each with a molecular weight of approximately 230 to 275 kDa, connected by two disulfide bonds at the C-terminus. This dimeric organisation is essential for its interaction and assembly capabilities.

Fibronectin is organised into distinct functional domains, each dedicated to a specific interaction. The most important among these are the assembly domain, essential for initiating fibrillogenesis, the cell-binding domain, the collagen-binding domain and the heparin- and fibrin-binding domain. This mosaic arrangement confers on fibronectin a central hub function within the extracellular matrix network, capable of connecting structural proteins, growth factors and cell-surface receptors.

Far from being a mere support element, fibronectin is a dynamic and mechanosensitive protein.

In the skin, fibronectin occupies a central position within the extracellular matrix. Owing to its capacity to interact simultaneously with membrane receptors and with other matrix components, it actively participates in cellular adhesion, migration and the three-dimensional organisation of dermal tissue. Its distribution is not homogeneous: it is preferentially concentrated at the dermo-epidermal junction, along vascular walls and in the dermal connective tissue, where it appears as fibrillar or amorphous deposits often associated with fibroblasts and collagen fibrils. Histological studies also show that fibronectin is more abundant in foetal skin than in adult skin, which is consistent with its role in tissues undergoing growth and reorganisation.

One of fibronectin’s major functions is the mediation of cell adhesion. This interaction relies primarily on integrins, transmembrane receptors expressed by fibroblasts, keratinocytes and endothelial cells. The cell-binding domain of fibronectin contains the RGD (Arg–Gly–Asp) sequence, notably recognised by integrins α5β1 and αVβ3. Engagement of these receptors enables the formation of adhesion complexes linking the extracellular matrix to the actin cytoskeleton.

This connection ensures the mechanical anchoring of cells, but it also triggers intracellular signalling cascades involved in the regulation of proliferation, survival and differentiation. Some studies in vitro indeed show that cell contact with matrix proteins such as fibronectin can modify their adhesion capacity and migratory activity, confirming that matrix composition directly influences cellular behaviour.

Fibronectin is also closely associated with cell migration phenomena, particularly in the contexts of tissue reorganisation. It can exhibit chemotactic activity towards certain cell types, notably fibroblasts and endothelial cells, and provide a transient adhesion substrate allowing cellular progression along an organised matrix. For information, chemotaxis refers to the property of certain cells being attracted or repelled by molecules.

Fibronectin is particularly involved during skin healing.

In the early stages of healing, fibronectin appears early within granulation tissue, often in association with fibrin, creating a provisional matrix that supports fibroblast and endothelial cell migration. As repair progresses and the collagenous matrix matures, fibronectin density decreases. It therefore plays a predominant role in the initial phases of remodelling, although it is present at all stages.

1. Haemostatic phase : Within the first minutes following injury, plasma fibronectin incorporates into the developing clot alongside fibrin. It enhances platelet aggregation and takes part in the signalling mechanisms associated with platelet activation. By contributing to the initial stabilisation of the clot, it also initiates the formation of a provisional fibrillar matrix essential for the continuation of the repair process.

2. Inflammatory phase : During the inflammatory phase, plasma fibronectin contributes to the formation of a transient matrix at the site of injury. This matrix facilitates the infiltration and organisation of immune cells involved in removing cellular debris and pathogens. In doing so, fibronectin indirectly aids the “clean-up” of the wound site.

3. Proliferative phase : During the proliferative phase, cellular fibronectin synthesised by fibroblasts assembles into a matrix network, notably in association with type I collagen. It promotes the migration of fibroblasts and endothelial cells and contributes to angiogenesis, that is to say the formation of new blood vessels, an essential step for supplying nutrients and oxygen to the tissue under reconstruction.

4. Remodelling phase : During remodelling, the provisional fibronectin-rich matrix is progressively reorganised and replaced by a denser, more stable collagenous matrix. Fibronectin contributes to the regulation of apoptosis in certain cells involved in repair, aiding the gradual normalisation of the tissue. However, excessive or persistent accumulation of fibronectin can promote overproduction of the extracellular matrix and contribute to the formation of hypertrophic scars.

Fibronectin is directly involved in the maintenance and restoration of tissue integrity.

Fibronectin is a dynamic protein whose expression and organisation evolve during cutaneous ageing.

Immunohistochemical analyses performed on skin biopsies from young and aged donors show that fibronectin is predominantly localised in the dermis, with stronger intensity in the papillary dermis than in the reticular dermis. The epidermis, in turn, exhibits very low fibronectin detection, irrespective of age. With ageing, a global decrease in dermal fibronectin is observed. This decline is particularly notable in the reticular dermis, while expression in the papillary dermis remains relatively stable, likely to preserve the integrity of the dermal-epidermal junction.

Beyond its quantity, ageing also affects the organisation of fibronectin.

In a replicative senescence model using human dermal fibroblasts, it was observed that the ability of fibronectin to form an organised fibrillar network in the extracellular matrix is diminished. This alteration of fibrillogenesis is also accompanied by disorganisation of the matrix network, which contributes to skin laxity and the appearance of wrinkles.

In fact, skin ageing is also influenced by environmental factors, notably the UV rays and the oxidative stress. These insults stimulate the expression of matrix metalloproteinases, enzymes capable of degrading various extracellular matrix components, including fibronectin. Fibronectin fragmentation disrupts its fibrillar organisation and compromises its interactions with integrins and collagen. This degradation contributes to a loss of dermal network coherence. A less organised matrix alters the mechanical forces exerted on fibroblasts and may reduce their ability to effectively synthesise structural proteins, notably collagen. A vicious cycle then ensues: matrix disorganisation impairs cellular function, further exacerbating matrix deterioration.

The quantitative reduction in fibronectin, combined with impaired fibrillogenesis and increased fragmentation, contributes to the progressive disorganisation of the dermis observed with ageing.

Note : The skin ageing is not simply a decline in collagen: it also involves modifications to the structural proteins of the extracellular matrix, such as fibronectin.

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