Mesenchymal stem cells and neovascularization: role of platelet-derived growth factor receptors

Abstract

There is now accumulating evidence that bone marrow-derived mesenchymal stem cells (MSCs) make an important contribution to postnatal vasculogenesis, especially during tissue ischaemia and tumour vascularization. Identifying mechanisms which regulate the role of MSCs in vasculogenesis is a key therapeutic objective, since while increased neovascularization can be advantageous during tissue ischaemia, it is deleterious during tumourigenesis. The potent angiogenic stimulant vascular endothelial growth factor (VEGF) is known to regulate MSC mobilization and recruitment to sites of neovascularization, as well as directing the differentiation of MSCs to a vascular cell fate. Despite the fact that MSCs did not express VEGF receptors, we have recently identified that VEGF-A can stimulate platelet-derived growth factor (PDGF) receptors, which regulates MSC migration and proliferation. This review focuses on the role of PDGF receptors in regulating the vascular cell fate of MSCs, with emphasis on the function of the novel VEGF-A/PDGF receptor signalling mechanism.

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Schematic diagrams highlighting potential mechanisms regulating PDGF receptor signalling.(A) MSC autocrine VEGF-A expression may regulate paracrine PDGF ligand stimulation of PDGF receptors, by VEGF-A competitively binding to PDGF receptors and competing with PDGF concentration gradients. (B) Modulation of VEGF-A induced PDGF receptor signalling specificity is likely to be multifactorial, depending in part on quantitative and qualitative differences, such as; (1) local oxygen concentration regulating VEGF-A expression, (2) matrix sequestration and retention of VEGF-A, (3) soluble VEGF-A level, (4) concentration of PDGF ligands, (5) integrin-matrix interactions, (6) local membrane-associated proteins, (7) recruitment of signalling molecules.

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MSCs have inherent capacity to rapidly form capillary-like structures. The ability for MSCs to form in vitro tube-like structures was determined by culturing MSCs on three-dimensional Matrigels or fibrin gels, under either normoxic (20%) or hypoxic (1%) oxygen levels for 4 hrs. Both Matrigel and fibrin induced capillary-like structure formation, with Matrigel and hypoxia promoting increased tube length and branching points. However, after 24 hrs (data not shown), normoxic or hypoxic conditions resulted in similar capillary-like structure organization. Images were taken using phase-contrast microscopy with a 10x objective lens.

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Schematic diagram showing distinct differences between PDGFRα and PDGFRβ signalling, which results in the regulation of contractile SM -actin filaments within MSCs. PDGF-AA induced PDGFRα signalling activates RhoA and increases cofilin phosphorylation via LIM kinase, resulting in enhanced SM α-actin filament polymerization. In addition, ROCK activates myosin light chain (MLC)-II ATPase activity, which is necessary for both SM α-actin and F-actin filament polymerization. In contrast, PDGF-BB induced PDGFRβ signalling increases RhoE, which inhibits ROCK activity, promoting SM α-actin filament depolymerization.