Hyaluronan and CD44 control of cell fate

• Main Author: Woods, Emma
• Published: Cardiff University 2016
• Subjects: 616.7; R Medicine (General)
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.704909

Fibrosis can be charactorised as abberent wound healing resulting from an increased presence of α-smooth muscle actin (αSMA)-rich, myofibroblasts and a continued influx of immune cell mediators. The pro-fibrotic and pro-inflammatory cytokines TGF-β1 and IL-1β, respectivley, have been implicated in fibrotic progression by activating hyaluronan (HA)/CD44-mediated pathways. CD44, the principal HA receptor, exists as multiple spliced variants which mediate multiple celluar functions through their association with HA. The aim of this Thesis was to investigate the expression and interactions of CD44 variants asociated with fibroblast activation induced by TGF-β1 or IL-1β. Multiple forms of CD44 spliced variants were identified in fibroblasts. Stimulation with TGF-β1 decreased the expression of all variants, whereas IL-1β-increased global CD44 expression. CD44s was the variant identified as essential for both TGF-β1 induction of myofibroblasts and IL-1β-induced monocyte binding to fibroblasts. CD147 is a matrix metaloproteinase (MMP) inducer that mediates receptor interactions within the plasma mebrane; and contributes to ECM re-arrangment in response to various stimuli. CD147-medaited-αSMA incorporation into F-actin stress fibres that were essential for the myofibroblast contractile phenotype. It associated with CD44s and the EDA-Fibronectin-associated integrin, α4β7, suggesting that through receptor interaction it mediated the mechanotransduction properties required for differentiation. Decreased expression of CD147 prevented intracellular activativation of ERK1/2, an essential kinase involved in mechanotransdction. These data suggest that CD44s regulates both a fibrotic and inflammatory response by fibroblasts through two separate mechanistic pathways. It also implicates CD44s in mechanotransduction, via its association with CD147. In conclusion, both CD44s and CD147 are essential mediators of fibrosis and further research into downstream mediators could lead to potential therapeutic targets to combat fibrotic progression.