Journal des complications et de la médecine du diabète

Epidermal Growth Factor based Therapy Promotes Intracellular Trafficking and Accumulation of its Receptor in the Nucleus of Fibroblasts from Diabetic Foot Ulcers

Abstract

Viviana Falcón-Cama, Maday Fernández-Mayola, Yssel Mendoza-Marí, Nelson Acosta-Rivero, Ariana García-Ojalvo, Ricardo Bringas-Pérez, Ivón Menéndez-Valdés, Mariuska Matos-Terrero, Lilianne López-Noudo, Rocío Garateix-Suárez, Karla Pereira-Yañez, Maritza González, Si

Objective: To gain a better understanding of the Epidermal Growth Factor (EGF) Receptor (EGFR) activation, trafficking and biological response in diabetic foot ulcers (DFU), exposed to recombinant human EGF via intra-ulcer infiltration as a healing alternative.

Methods: We studied by immunoelectron microscopy the intracellular localization of the EGFR and Proliferating Cell Nuclear Antigen (PCNA) in fibroblast-like cells (FLC) from granulation tissue of DFU patients, collected before and at different time points after EGF treatment.

Results: EGF therapy appears to increase EGFR immunolabeling. At early time-points, EGFR labeling is observed predominantly in the nucleus, suggesting a fast EGFR internalization and nuclear translocation. Interestingly EGFR is also detected in the mitochondrial outer membrane. PCNA expression and trafficking were also detected in a time-dependent manner after EGF infiltration.

Conclusion: Differential subcellular distribution of EGFR and PCNA and accumulation in the nucleus, in a timepoint specific manner, supports the induction of an EGF-mediated activation program that is sustained for at least 24 hours after the EGF administration. These findings substantiate the therapeutic ability of EGF to restore the healing process in DFU.