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Aging fibroblasts resist phenotypic maturation because of impaired hyaluronan-dependent CD44/epidermal growth factor receptor signaling

Simpson, Russell M. L., Wells, Alan, Thomas, David William, Stephens, Philip, Steadman, Robert and Phillips, Aled Owain 2010. Aging fibroblasts resist phenotypic maturation because of impaired hyaluronan-dependent CD44/epidermal growth factor receptor signaling. American Journal of Pathology 176 (3) , pp. 1215-1228. 10.2353/ajpath.2010.090802

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Abstract

Fibroblast differentiation into myofibroblasts is a key event during normal wound repair. We have previously demonstrated an age-related defect in this process associated with impaired synthesis of hyaluronan (HA) synthase (HAS) 2 but failed to prescribe its role in a mechanistic sense. Here we demonstrate that in addition to HAS2, there is loss of EGF receptor (EGF-R) in aged cells, and both are required for normal fibroblast functionality. Analysis of molecular events revealed that in young cells, transforming growth factor (TGF)-beta 1-dependent phenotypic activation uses two distinct but cooperating pathways that involve TGF-beta receptor/Smad2 activation and EGF-mediated EGF-R/extracellular signal-regulated kinase (ERK) 1/2 signaling, and the latter is compromised with in vitro aging. Pharmacological inhibition of any of the five intermediates (TGF-beta receptor, Smad2, EGF, EGF-R, and ERK1/2) attenuated TGF-beta 1 induction of alpha-smooth muscle actin. We present evidence that the HA receptor CD44 co-immunoprecipitates; with EGF-R after activation by TGF-beta 1. This interaction is HA-dependent because disruption of HA synthesis abrogates this association and inhibits subsequent ERK1/2 signaling. in aged fibroblasts, this association is lost with resultant suppression of ERK1/2 activation. Forced overexpression of EGF-R and HAS2 in aged cells restored TGF-beta 1-mediated HA-CD44/EGF-R association and alpha-smooth muscle actin induction. Taken together, these results demonstrate that HA can serve as a signal integrator by facilitating TGF-beta 1-mediated CD44-EGF-R-ERK interactions and ultimately fibroblast phenotype. We propose a model to explain this novel mechanism and the functional consequence of age-dependent dysregulation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Dentistry
Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QH Natural history > QH301 Biology
R Medicine > RB Pathology
Publisher: Elsevier
ISSN: 0002-9440
Last Modified: 04 Jun 2019 20:33
URI: http://orca-mwe.cf.ac.uk/id/eprint/16072

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