The roles of platelet clec-2 and podoplanin in skin wound healing

Wichaiyo, Surasak (2019). The roles of platelet clec-2 and podoplanin in skin wound healing. University of Birmingham. Ph.D.

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Abstract

Platelet-expressed C-type lectin-like receptor-2 (CLEC-2) and glycoprotein (GP)VI play important roles in inflammation, in particular inflammatory haemostasis in the skin. The CLEC-2-ligand, podoplanin, is upregulated in the inflamed and wounded skin, but the role of the CLEC-2-podoplanin interaction and the signalling downstream of podoplanin in the repair process is unclear. I have addressed these questions by investigating skin wound healing in wild-type (WT) mice, transgenic mice that lack platelet GPVI or CLEC-2 or both receptors (double knockout; DKO), and podoplanin cytoplasmic tail-deficient (PdpnCyto) mice. Deletion of both CLEC-2 and GPVI impairs vascular integrity in the skin resulting in accelerated wound healing. The beneficial effect was due to increased plasma leakage in the tissue that promoted fibrin generation, enhanced re-epithelialisation and angiogenesis, and decreased immune cell infiltration. Accelerated wound healing also led to smaller scar formation. This healing phenotype is not due to developmental defects in DKO animals as similar results were obtained in podoplanin-blocking antibody-injected GPVI-deficient mice. Wound healing is independent of the signalling downstream of podoplanin as PdpnCyto mice had similar healing kinetics compared to WT mice. PdpnCyto mice were however capable of upregulating podoplanin during wound healing, suggesting further application of this model in inflammatory settings. Alongside wound repair, the PdpnCyto mice were characterised. I have shown that the cytoplasmic tail is dispensable for the separation of blood and lymphatic vessels. In addition, I have used a metabolomics approach to reveal an increase in M1 pro-inflammatory metabolites, i.e. glycolysis and inducible nitric oxide synthase (iNOS)-mediated arginine pathway, in bone marrow-derived podoplanin-deficient macrophages, which possibly support the anti-inflammatory activity of podoplanin in macrophages.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):