Interactions of mesenchymal stromal cells with their microenvironment

Ward, Lewis Stuart Corey (2018). Interactions of mesenchymal stromal cells with their microenvironment. University of Birmingham. Ph.D.

Preview

Ward18PhD.pdf
PDF - Accepted Version
Download (3MB)

Abstract

Mesenchymal stromal cells (MSC) suppress the inflammatory infiltrate through crosstalk with neighbouring endothelium. However, this response is lost at chronic inflammatory sites where stromal cells instead support leukocyte recruitment and upregulate expression of podoplanin. The mechanism and function by which this inflammatory phenotype is established is unknown. We hypothesise that MSC modulation of endothelium is also altered by exposure to inflammatory cytokines, and that expression of podoplanin confers an invasive phenotype, enabling the interaction of these perivascular MSC with circulating platelets.
MSC resisted functional transformation during acute or prolonged exposure to tumour necrosis factor alpha, instead maintaining their ability to suppress neutrophil recruitment in a flow-based assay. Expression of podoplanin promoted MSC migration through Ras-related C3 botulinum toxin substrate dependent signalling, enabling perivascular MSC to interact with cells confined to the circulation. Indeed, podoplanin induced the activation of platelets from flow through MSC protrusions in the endothelial lining.
The retention of MSC suppressive function under inflammatory conditions supports their use in equivalent environments for therapy. However, the implications of platelet CLEC-2 activation by its ligand, podoplanin on inflamed stroma have yet to be elucidated and warrant further investigation, with specific focus drawn to the pathophysiology of thromboinflammation and associated disorders.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):