Thymosin β4 (Tβ4) is a 43 amino acid peptide encoded by the Tmsb4x gene located on the X-chromosome. It has previously been shown to act as a secreted factor from the myocardium to the overlying epicardium of the developing murine heart, to mediate transformation of epicardial derived progenitor cells (EPDCs) into the coronary vasculature. This PhD project seeks to build on these studies and characterises the function of Tβ4 in the developing systemic vasculature, using the mouse as a model system. Expression analyses demonstrated specific localisation of Tβ4/Tβ4 in the endothelial cells of the embryonic vasculature. In order to ascertain the function of vascular Tβ4, global and endothelial cell specific in vivo Tβ4 loss of function models were examined. Both global and endothelial-specific Tβ4 mutant embryos displayed a reduced recruitment of vascular mural cells to developing blood vessels. Detailed phenotypic examination revealed that the mural cell deficit could be attributed to impaired differentiation of mature mural cells from undifferentiated mesoderm. This process was modelled in vitro, and it was discovered that treatment of the mural progenitor cell lines 10T1/2 and A404 with exogenous Tβ4 could promote their differentiation into mural cells. This process correlated with an increase in Smad phosphorylation and increased activity of the TGF-β pathway. Decreased levels of TGF-β target genes in vivo in Tβ4β null embryos indicated that TGF-β signalling was perturbed in the absence of Tβ4. These findings suggest a model whereby Tβ4 is secreted by the developing endothelium to stimulate the differentiation of uncommitted mesoderm into mature peri-vascular mural cells, via activation of the TGF-β pathway in the target cell population. As a consequence, Tb4 plays an essential role in vascular stability through mural cell support which has implications for vascular dysfunction in disease.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:587610 |
| Date | January 2011 |
| Creators | Rossdeutsch, A. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1333963/ |
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