What role does fibronectin play in the skin?

Key points to remember.

Fibronectin is an extracellular matrix glycoprotein, involved in cell adhesion, migration, and the structural organization of the dermis.
Fibronectin acts as an interface between cells and extracellular matrix components such as collagen, thereby contributing to tissue cohesion.
During wound healing, fibronectin plays an early role by participating in the formation of a provisional matrix that facilitates cell migration and angiogenesis.
With age, the amount of fibronectin decreases in the dermis, while its fibrillar organization becomes less efficient.

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What is fibronectin?

Fibronectin is first and foremost an architectural protein of the dermal extracellular matrix.

It is a high molecular weight glycoprotein (≈ 500–600 kDa in its dimeric form). It belongs to the structural components of the extracellular matrix and has a remarkable interaction capacity: it binds to integrins, the transmembrane receptors on the cell surface, but also to other matrix proteins, such as the collagen, elastin or fibrin. This binding versatility gives it the function of a platform for anchoring and integration of 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 and embryonic development.

Structure de la matrice extracellulaire. — Structure of the extracellular matrix.
Source: OLIVIA A. G. & al. Skin-on-a-chip technology: Microengineering physiologically relevant in vitro skin models. Pharmaceutics (2022).

In vertebrates, there are two main forms of fibronectin, derived from a single gene but differentiated by alternative pre-mRNA splicing mechanisms.

The plasma fibronectin, which is soluble, is synthesized by hepatocytes and circulates in blood plasma at an average concentration of about 300 µg/mL. It is involved in hemostasis and early tissue repair by binding to fibrin at injury sites.
The cellular fibronectin, insoluble, is a major component of the extracellular matrix. It is secreted primarily 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 via an integrin-dependent process.

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

Structure de la fibronectine (chaque domaine a des sites de liaison pour les récepteurs cellulaires et les molécules de la matrice extracellulaire). — Structure of fibronectin (each domain features binding sites for cell-surface receptors and extracellular matrix molecules).
Source: BADYLAK S. F. & al. Extracellular matrix as a bioscaffold for tissue engineering. Tissue Engineering (2023).

Fibronectin is organized into distinct functional domains, each specialized for a particular interaction. Among the most important are the assembly domain, essential for the initiation of fibrillogenesis; the cell-binding domain; the collagen-binding domain; and the heparin- and fibrin-binding domain. This mosaic organization endows fibronectin with a central hub in the matrix network, capable of connecting structural proteins, growth factors, and cell-surface receptors.

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

What role does fibronectin play in the skin?

In the skin, fibronectin occupies a central position within the extracellular matrix. Thanks to its ability to simultaneously interact with membrane receptors and other matrix components, it actively contributes to cell adhesion, migration, and the three-dimensional organization of dermal tissue. Its distribution is not uniform: it is preferentially concentrated at the dermoepidermal junction, along vascular walls, and within 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 fetal skin than in adult skin, consistent with its role in tissues undergoing growth and reorganization.

One of the major functions of fibronectin is to mediate 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 recognized by α5β1 and αVβ3 integrins. Engagement of these receptors enables the formation of adhesion complexes linking the extracellular matrix to the actin cytoskeleton.

Complexe d'adhésion avec la fibronectine reliant la matrice extracellulaire au cytosquelette d'actine. — Adhesion complex with fibronectin linking the extracellular matrix to the actin cytoskeleton.
Source: Les protéines d’adhérence de la matrice extracellulaire. Ressources numériques en biologie.

This connection ensures the mechanical anchoring of cells, but it also triggers intracellular signaling cascades involved in the regulation of proliferation, survival, and differentiation. Some studies in vitro demonstrate that cell contact with matrix proteins such as fibronectin can alter their adhesive capacity and migratory activity, confirming that matrix composition directly influences cell behavior.

Some definitions.

Fibrillogenesis : Biological process by which soluble proteins, such as fibronectin or collagen, assemble into organized fibrils within the extracellular matrix.
Heparin : A sulfated glycosaminoglycan closely related to heparan sulfates, primarily known for its anticoagulant properties and used experimentally to study certain matrix interactions.
Fibrin : Protein involved in blood coagulation, forming an insoluble network that stabilizes the clot and participates in wound healing.
Dermal-epidermal junction : Specialized interface between the epidermis and the dermis, ensuring adhesion and exchange between these two skin compartments.
Fibroblasts : Primary cells of the dermis responsible for the synthesis of extracellular matrix components, notably collagen, elastin, and fibronectin.
Integrins : Transmembrane receptors that link the extracellular matrix to the intracellular cytoskeleton, playing a central role in cell adhesion and signaling.
Actin Cytoskeleton : An intracellular network of actin filaments involved in maintaining cell shape, adhesion, and migration.

Fibronectin is also tightly linked to cell migration phenomena, particularly in tissue reorganization contexts. It can exert chemotactic activity toward specific cell types—especially fibroblasts and endothelial cells—and provide a transient adhesion substrate that enables cells to move along an organized matrix. For reference, chemotaxis refers to the property of certain cells to be attracted to or repelled by particular molecules.

Fibronectin is particularly involved during skin healing.

In the early stages of wound healing, fibronectin appears early in the granulation tissue, often in association with fibrin, forming a provisional matrix that supports the migration of fibroblasts and endothelial cells. As repair progresses and the collagen matrix takes shape, fibronectin density decreases. Therefore, it plays a predominantly early role in remodeling, although it is present at every stage.

Hemostasis phase : Within the first minutes after injury, plasma fibronectin integrates into the forming clot alongside fibrin. It promotes platelet aggregation and participates in the signaling mechanisms associated with platelet activation. By contributing to the initial stabilization of the clot, it also initiates the formation of a provisional fibrillar matrix essential for the continuation of the repair process.
Inflammatory phase : During the inflammatory phase, plasma fibronectin contributes to the formation of a provisional matrix at the injury site. This matrix facilitates the infiltration and organization of immune cells involved in the removal of cellular debris and pathogens. In this way, fibronectin indirectly participates in the “cleanup” of the wound site.
Proliferative phase : During the proliferative phase, cell fibronectin synthesized by fibroblasts assembles into a matrix network, particularly in association with type I collagen. It promotes the migration of fibroblasts and endothelial cells and contributes to angiogenesis—that is, the formation of new blood vessels—an essential step for delivering nutrients and oxygen to the tissue under reconstruction.
Remodeling phase : During remodeling, the provisional fibronectin-rich matrix is gradually reorganized and replaced by a denser, more stable collagen matrix. Fibronectin helps regulate apoptosis in certain repair-related cells, contributing to the tissue’s progressive normalization. However, excessive or persistent fibronectin accumulation can promote overproduction of the extracellular matrix and contribute to the formation of hypertrophic scars.

Le rôle de la fibronectine aux différentes étapes de la cicatrisation. — The role of fibronectin in the various stages of wound healing.
Source: WANG K. & al. Fibronectin in development and wound healing. Advanced Drug Delivery Reviews (2021).

Fibronectin is directly involved in maintaining and restoring tissue integrity.

How does fibronectin change with age and environmental stressors?

Fibronectin is a dynamic protein whose expression and organization evolve during skin aging.

Immunohistochemical analyses performed on skin biopsies from young and elderly donors show that fibronectin is predominantly localized in the dermis, with a more pronounced signal in the papillary dermis than in the reticular dermis. The epidermis, meanwhile, displays very low fibronectin detection regardless of age. With aging, a global decrease in dermal fibronectin is observed. This decline is particularly pronounced in the reticular dermis, while expression in the papillary dermis remains relatively stable, likely to preserve the integrity of the dermal-epidermal junction.

Niveaux de fibronectine dans des biopsies de donneurs jeunes et âgés. — Fibronectin levels in biopsies from young and aged donors.
Source: PICOT C. R. & al. Impaired incorporation of fibronectin into the extracellular matrix during aging exacerbates the senescent state of dermal cells. Experimental Cell Research (2024).

Beyond its quantity, aging also affects the organization of fibronectin.

In a replicative senescence model using human dermal fibroblasts, it was observed that fibronectin’s ability to form an organized fibrillar network in the extracellular matrix is diminished. This alteration of fibrillogenesis is also accompanied by disorganization of the matrix network, contributing to skin laxity and wrinkle formation.

In fact, skin aging is also influenced by environmental factors, notably the UV rays and the oxidative stress. These assaults stimulate the expression of matrix metalloproteinases, enzymes capable of degrading several extracellular matrix components, including fibronectin. Fibronectin fragmentation disrupts its fibrillar organization and compromises its interactions with integrins and collagen. This degradation contributes to a loss of coherence of the dermal network. A less organized matrix alters the mechanical stresses exerted on fibroblasts and can reduce their ability to efficiently synthesize structural proteins, particularly collagen. A vicious cycle then ensues: matrix disorganization impairs cellular function, which further exacerbates matrix deterioration.

The quantitative reduction in fibronectin, associated with impaired fibrillogenesis and increased fragmentation, contributes to the progressive disorganization of the dermis observed with age.

Remark : The skin aging is not limited to a simple decrease in collagen: it also involves a modification of the structural proteins of the extracellular matrix, such as fibronectin.