Investigation of Syndecan-2 selected purified human umbilical cord mesenchymal stromal cells as a novel therapy for liver fibrosis. (360G-Wellcome-108741_Z_15_Z)

The aim of this project is to examine the ability of purified syndecan-2 (SDC2)-selected human umbilical-cord mesenchymal stromal cells (MSC) to resolve established fibrosis, thus determining their potential as a clinical treatment for patients with advanced liver fibrosis. I will firstly determine the effect of SDC2-selected MSC on the resolution of liver fibrosis by injecting them into 3 different murine models of established liver fibrosis. I will explore the mechanistic role of SDC2 ex pression by use of MSC with up- and down-modulated SDC2 expression (achieved by adenoviral transfection), in a model of CCl4-induced fibrosis. I will determine how SDC2-expression affects the anti-fibrotic phenotype by comparing the secretory cytokine signature of cultured MSC after modulation of SDC2 expression. I will then establish how SDC2-selected MSC affect murine hepatic stellate cells (HSC) in a model of CCl4-induced fibrosis by the use of transgenic hepatic stellate cell reporter mic e This will allow co-localisation of HSC with labelled MSC to be studied, and also cell sorting of HSC to determine their fate and activational status. I will subsequently use selective cytokine neutralisation during co-culture of MSC with murine and human HSC to ascertain the MSC effectors that determine HSC function.