The skin is the body’s largest organ and functions as the primary interface between the internal environment and the external world. It is also the organ most visibly affected by chronological aging and cumulative environmental damage. In both intrinsic aging—characterized by the thinning of the dermis, loss of collagen, and degradation of elastic fibers—and extrinsic photoaging—driven by ultraviolet radiation—there is a progressive imbalance between the anabolism and catabolism of extracellular matrix (ECM) proteins [1]. This imbalance leads to wrinkles, altered pigmentation, loss of elasticity, impaired texture, and diminished radiance.
The maintenance and repair of healthy skin are regulated by an intricate network of signaling molecules, with growth factors serving as pivotal regulators [2]. These proteins serve as primary regulators of cellular activities, guiding the migration, proliferation, and differentiation of fibroblasts, keratinocytes, and endothelial cells, while also overseeing the synthesis and remodeling of collagen, elastin, and other extracellular matrix components [3].
Epidermal Growth Factor (EGF): Driving Keratinocyte Proliferation and Wound Closure
Epidermal growth factor (EGF) is a 53-amino acid polypeptide that serves as a potent mitogen for various cell types [4]. In the skin, EGF is primarily synthesized by platelets, macrophages, and fibroblasts. It exerts its effects by binding to the EGF receptor (EGFR) on target cells, thereby activating downstream signaling pathways such as PI3K/AKT and RAS/RAF/MAPK [5].
EGF plays an essential role in re-epithelialization, the process by which new epidermal cells migrate across a wound bed to restore the skin barrier [6]. It stimulates keratinocyte proliferation and migration from the wound edges, thereby accelerating wound closure and reducing the risk of infection. Furthermore, EGF signals cellular proliferation and the production of structural proteins such as collagen, rendering it fundamental to both wound healing and overall skin preservation [4].
For skin rejuvenation, EGF promotes epidermal thickening and helps restore barrier integrity. Research has demonstrated that EGF can augment collagen synthesis in granulation tissue by stimulating fibroblast proliferation [7]. In conjunction with other growth factors, EGF guarantees that the final phases of skin regeneration occur effectively [8].
Fibroblast Growth Factors (FGFs): Regulating Dermal Repair and Collagen Production
The fibroblast growth factor family comprises numerous signaling proteins that play diverse roles in skin biology. Among these, basic fibroblast growth factor (FGF-2, also referred to as bFGF) is one of the most extensively researched in the context of dermal regeneration.
Endothelial cells, macrophages, and monocytes secrete FGF-2 [5]. It promotes fibroblast proliferation and migration, stimulates angiogenesis (the formation of new blood vessels), and enhances collagen deposition, thereby contributing to tissue regeneration [6].
In animal models of wound healing, FGF-2 has been demonstrated to enhance re-epithelialization, augment angiogenesis, and promote collagen deposition within the wound bed [5].
In the aging dermis, decreased FGF activity contributes to reduced fibroblast function and collagen synthesis. FGFs have garnered significant research interest due to their role as regulatory proteins mediating critical signaling pathways and influencing cellular regeneration and repair processes [9].
Platelet-Derived Growth Factor (PDGF): Recruiting and Activating Dermal Cells
PDGF constitutes a family of growth factors released by platelets in response to tissue injury, as well as by keratinocytes, macrophages, and endothelial cells [5]. It serves as a potent chemoattractant for fibroblasts, smooth muscle cells, and other cell types crucial to granulation tissue formation.
Once recruited, PDGF stimulates fibroblast proliferation and activation, thereby promoting the deposition of new extracellular matrix (ECM) and facilitating wound contraction [6]. Additionally, PDGF supports angiogenesis and synergizes with other growth factors to direct the healing process across its subsequent phases [10].
In the context of skin rejuvenation, PDGF facilitates the remodeling of the dermal matrix by promoting the replacement of fragmented and disorganized collagen with newly synthesized, well-aligned fibers. Its capacity to recruit and activate dermal fibroblasts renders it a valuable component in regenerative skin treatments.
Vascular Endothelial Growth Factor (VEGF): Restoring the Dermal Microcirculation
VEGF functions as the principal catalyst for angiogenesis. It is synthesized by platelets, macrophages, keratinocytes, and endothelial cells, facilitating the development of new blood vessels from the pre-existing microvasculature [5].
Adequate angiogenesis is essential for tissue repair, as it guarantees that the healing tissue acquires sufficient oxygen and nutrients. In photoaged and chronologically aged skin, the dermal microcirculation becomes sparse and dysfunctional, resulting in impaired nutrient delivery and delayed wound healing.
VEGF acts by binding to receptors on endothelial cells, thereby promoting their proliferation, migration, and the formation of new capillary networks [6]. Animal studies have confirmed that VEGF promotes angiogenesis, collagen deposition, and macrophage polarization in wound models, thereby contributing significantly to re-epithelialization [5].
Transforming Growth Factor-Beta (TGF-β): ECM Homeostasis and Remodeling
TGF-β is a pleiotropic cytokine that plays a central role in regulating inflammation, collagen deposition, and tissue remodeling during wound healing [11]. It is released by platelets, keratinocytes, macrophages, and lymphocytes and acts on a wide range of cell types, thereby influencing cell-cycle regulation, matrix synthesis, and immune function.
During the proliferative and remodeling phases of wound healing, TGF-β encourages the synthesis of collagen types I and III by dermal fibroblasts, while concurrently inhibiting the activity of matrix metalloproteinases (MMPs) involved in extracellular matrix (ECM) degradation.
The balance between collagen synthesis and breakdown is a crucial factor influencing skin thickness and mechanical properties.
Nevertheless, dysregulation of TGF-β signaling may pose difficulties. An overactivation of TGF-β has been associated with the onset of fibrotic disorders and keloid formation. Conversely, decreased TGF-β activity in aging skin contributes to lower collagen production and compromised tissue regeneration [11].
Maintaining normal TGF-β expression is therefore important for preserving ECM homeostasis, promoting collagen synthesis, and reducing inflammatory factor expression [13].
The Role of Growth Factors in Clinical Skin Rejuvenation
Therapeutic methodologies leveraging the regenerative potential of growth factors have transitioned from experimental hypotheses to established clinical procedures. Platelet-rich plasma (PRP), an autologous platelet concentrate rich in PDGF, TGF-β, VEGF, EGF, and other growth factors, has been extensively studied for facial rejuvenation.
A systematic review conducted in 2025, encompassing twenty studies involving 514 patients, identified significant enhancements following PRP/PRF treatment. Specifically, improvements were observed in 80% of studies in skin thickness, 75% in skin elasticity, and 40% in wrinkles, with no serious adverse events reported [14].
Topical formulations containing human fibroblast growth factors have also demonstrated significant improvement in facial wrinkling in prospective randomized trials [15].
Conclusion
A single growth factor does not drive skin regeneration; rather, it is governed by a meticulously coordinated network of signaling molecules, each fulfilling a specific function. EGF facilitates re-epithelialization, FGF promotes dermal repair and collagen synthesis, PDGF attracts and activates fibroblasts, VEGF restores dermal microcirculation, and TGF-β orchestrates extracellular matrix homeostasis and remodeling.
Collectively, these growth factors govern the migration, proliferation, differentiation, and synthetic activity of the cells responsible for maintaining healthy skin.
References
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