title: Transdifferentiated circulating monocytes release exosomes containing 14-3-3 proteins with matrix metalloproteinase-1 stimulating effect for dermal fibroblasts.
abstract: Fibroblasts are major cellular components of healing wounds. In this regard, it remains to be fully understood how different paracrine signals may influence the final collagen/matrix metalloproteinase (MMP) balance in resident fibroblasts. Our previous reports have demonstrated that circulating stem cells and monocytes can be transdifferentiated into "keratinocyte-like cells" under certain culture conditions. These transformed cells are able to stimulate MMP-1 expression in dermal fibroblasts. However, the underlying mechanism of this cell-to-cell interaction is unknown. This study describes exosomes as a major delivery system that keratinocyte-like cells use to release proteins into the conditioned media. The exosomes exhibited distinctive size, density, and saucer-like morphology. Using PKH-26 and GFP-adenovirus infection, we demonstrated that exosomes are able to fuse and then release their protein content into dermal fibroblasts. Mass spectrometry and Western blotting identified five 14-3-3 isoforms (beta, gamma, epsilon, tau, and zeta) as MMP-1 stimulating factors for dermal fibroblasts. Immunoprecipation assays confirmed that these 14-3-3 isoforms account for almost the entire MMP-1 up-regulation induced by exosomes. In summary, our results demonstrated that circulating monocytes stimulated to be transformed into "keratinocyte-like cells" could promote an anti-fibrogenic commitment of dermal fibroblasts via exosomal 14-3-3 proteins.
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Abelardo
authors.initials: A
authors.lastname: Medina
authors.forename: Aziz
authors.initials: A
authors.lastname: Ghahary
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology*; D055354:Exosomes / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D007223:Infant; D020781:Matrix Metalloproteinase 1 / Q000502:physiology*; D046529:Microscopy, Electron, Transmission; D009000:Monocytes / Q000166:cytology*; D015854:Up-Regulation
chemical_list: D048948:14-3-3 Proteins; D020781:Matrix Metalloproteinase 1