Year: 2017
Type: dissertation
Abstract: Fibroblasts are a type of cell which forms the structural framework of the connective tissue \nand are key players of wound closure, fibrosis and cancer. These cells experience mechanical \nperturbations due to matrix remodelling and interstitial fluid movement. Chemical signals \nfrom the tissue microenvironment such as Transforming growth factor β1 (TGF-β1) promote \ndifferentiation of fibroblasts to a myofibroblastic phenotype marked by enhanced expression \nof α-smooth muscle actin (α-SMA) rich stress fibres. However most of the evidence for this \nhas been derived in static cultures which do not fully recapitulate the mechanically dynamic \nenvironment in vivo. \n \nThe response of primary human fibroblasts to physiological levels of fluid movement and \nchemical perturbations from TGF-β1 is examined in this study. Findings show that fluid flow \ninduced widespread changes in gene expression compared to static cultures and up-regulated \ngenes such as α-SMA and Collagen 1A1. Surprisingly the combination of flow and \nexogenous TGF-β1 resulted in reduced myofibroblast differentiation. \n \nMyofibroblastic differentiation under flow was partially inhibited by follistatin-288 and \nblocked by TGF-β1 supplementation. This was associated with caveolin-mediated \ninternalisation of TGF-β receptor type II. These findings suggest that fluid flow modulates \nfibroblast response to pro-differentiation signals such as TGF-β1. We propose that this may \nbe a novel mechanism by which mechanical forces buffer responses to chemical signals in \nvivo, maintaining a context-specific fibroblast phenotype.
Author: Sadhvi Nithiananthan
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2626270244