Epidermal growth factor improves the migration and contractility of aged fibroblasts cultured on 3D collagen matrices

Abstract

Abstract. Epidermal growth factor (EGF) plays a critical role in fibroblasts by stimulating the production of collagen and supports cell renewal through the interaction between keratinocytes and fibroblasts. It is well known that the contractile activity of fibroblasts is required for the remodeling of the extracellular matrix (ECM), which contributes to skin elasticity. However, the role of EGF in the contraction of aged fibroblasts under 3-dimensional (3D) culture conditions is not yet fully understood. In the present study, we demonstrated that young fibroblasts spread and proliferated more rapidly than aged fibroblasts under 2-dimensional (2D) culture conditions. Cell migration assay using a nested collagen matrix revealed that the migration of young fibroblasts was also greater than that of aged fibroblasts under 3D culture conditions. However, the addition of recombinant human EGF (rhEGF) resulted in the enhanced migration of aged fibroblasts; the migration rate was similar to that of the young fibroblasts. The aged fibroblasts showed decreased cluster formation compared with the young fibroblasts on the collagen matrix, which was improved by the addition of rhEGF. Furthermore, cell contraction assay revealed that the basal contractility of the aged fibroblasts was lower than that of the young fibroblasts; however, following treatment with rhEGF, the contractility was restored to levels similar or even higher to those of the young fibroblasts. Taken together, our results suggest that rhEGF is a potential renewal agent that acts to improve the migration and contraction of aged fibroblasts more efficiently than young fibroblasts under 3D culture conditions; thus, EGF may have valuable regenerative effects on aged skin. IntroductionSkin aging is a biological process that involves cutaneous aging and photo-aging, both of which are associated with harmful environmental insults, including UV radiation, heat, gravity and smoking (1). More specifically, cutaneous aging comprises the loss of elasticity, which causes wrinkling of the skin through the deprivation of extracellular matrix (ECM) (2,3). Treatments for skin aging include herbal extracts, vitamins and growth factors, which have been established to promote ECM protein synthesis and to reduce degradation enzymes of the ECM, thereby delaying the progression of skin aging (4-6).Several growth factors and cytokines are involved in the regulation of skin homeostasis and development (7), all of which are important for the preservation of cutaneous functions by acting as autocrine and paracrine factors (8). Furthermore, several recombinant cytokines and growth factors are currently used in clinical practice to treat patients with various diseases. These cytokines and growth factors control the regulatory functions of several powerful and complex signaling networks. Among these, the epidermal growth factor (EGF) and its receptor (EGFR) command a wide spectrum of diverse biological effects, including cellular proliferation, differentiation, wound healing, hair folli...

Scars or Regeneration?—Dermal Fibroblasts as Drivers of Diverse Skin Wound Responses

“…Aberrant persistence of EGFR signaling can lead to hypertrophic scars or keloid scars [31,32], partially due to paracrine upregulation of EGFR on fibroblasts [33]. Aged dermal fibroblasts exhibit reduced EGFR expression, and this decline correlates with decreased responsiveness to EGFR mitogenic signaling, manifested in delayed healing and reduced scarring [30,34].…”

Extracellular Matrix Rigidity-dependent Sphingosine-1-phosphate Secretion Regulates Metastatic Cancer Cell Invasion and Adhesion

“…The increase in cell contractility with MDA-CM was confirmed by the measurement of stress-related collagen matrix contraction (SRMC) which is a typical method for evaluating cell contractility induced by mechanical tension 29 . SRMC under MDA-CM increased profoundly, while the extent of SRMC with 10A-CM was similar to that of control medium ( Fig.…”

Growth factor pathways in hypertrophic scars: Molecular pathogenesis and therapeutic implications

“…This study also indicated EGF-MSCs as a useful cell therapy approach for hypertrophic scars. Interestingly, a recent investigation demonstrated that rhEGF improved the migration and contraction of aged fibroblasts more efficiently than young fibroblasts under three-dimensional culture conditions [76]. These findings implied that rhEGF might have regenerative effects on aged skin and highlighted the therapeutic value of EGF for hypertrophic scars in aged populations.…”