Aging fibroblasts present reduced epidermal growth factor (EGF) responsiveness due to preferential loss of EGF receptors

Wound healing is compromised in aging adults in part due to decreased respo nsiveness of fibroblasts to extracellular signals. However, the cellular me chanisms underlying this phenomenon are not known. Aged dermal fibroblasts with reduced remaining replicative capacities demonstrated decreased epider mal growth factor (EGF)-induced cell migrative and cell proliferative capac ities, as reported previously. Thus, as cells approach senescence, programm ed in vivo or in vitro, EGF responsiveness is preferentially lost. To defin e the rate-limiting signaling event, we found that the activity of two diff erent EGF receptor (EGFR)-signaling pathways to cell migration (phospholipa se-C gamma) and/or mitogenesis (extracellular signal/regulated-mitogen-acti vated kinases) were decreased in near senescent cells despite unchanged lev els of effector molecules. Aged cells presented decreased levels of EGFR, a lthough insulin receptor and transferrin receptor levels were relatively un changed. EGFR, mRNA levels and production of new transcripts decreased duri ng aging, suggesting that this preferential loss of EGFR was due to diminis hed production, which more than counteracts the reduced ligand-induced rece ptor loss. Since these data suggested that the decrement in EGF was rate-li miting, higher levels of EGFR were established in near senescent cells by e lectroporation of EGFR cDNA. These cells presented higher levels of EGFR an d recovered their EGF-induced migration and proliferation responsiveness. T hus, the defect in EGF responsiveness of aged dermal fibroblasts is seconda ry to reduced EGFR message transcription. Our experimental model suggests t hat EGFR gene delivery might be an effective future therapy for compromised wound healing.