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

Ball SG, Shuttleworth CA, Kielty CM - J. Cell. Mol. Med. (2007 Sep-Oct)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: UK Centre for Tissue Engineering, Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, The University of Manchester, Manchester, UK.

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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Related in: MedlinePlus

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.
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fig03: 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.

Mentions: MSCs normally contain low levels of myocardin transcript, but when transfected with an adenovirus expressing myocardin, specifically induced SM myosin heavy chain [85]. Activation of the small GTPase RhoA has been shown to promote SM α-actin gene expression, which was mediated by serum response factor [86]. Our studies have demonstrated that MSCs have a high ratio of PDGFRα : PDGFRβ and that PDGFRα signalling activated RhoA, resulting in enhanced SM α-actin transcription and filament polymerization [10]. PDGFRα phosphorylation activates RhoA which, through Rho-associated kinase (ROCK)-dependent cofilin phosphorylation and myosin light chain kinase-dependent pathways, enhances SM α-actin filament polymerization. In contrast, PDGFRβ signalling inhibits SM α-actin filaments by up-regulating RhoE, which inhibits ROCK and by PDGF-BB induced cofilin-mediated filament destabilization [10]. Thus the cell surface PDGFRα : PDGFRβ ratio and ligand concentration are critical determinants for commitment to a vascular SMC fate. A diagram showing PDGF receptor regulation of SM α-actin filament polymerization in MSCs, is shown in Figure 3.


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

Ball SG, Shuttleworth CA, Kielty CM - J. Cell. Mol. Med. (2007 Sep-Oct)

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401270&req=5

fig03: 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.
Mentions: MSCs normally contain low levels of myocardin transcript, but when transfected with an adenovirus expressing myocardin, specifically induced SM myosin heavy chain [85]. Activation of the small GTPase RhoA has been shown to promote SM α-actin gene expression, which was mediated by serum response factor [86]. Our studies have demonstrated that MSCs have a high ratio of PDGFRα : PDGFRβ and that PDGFRα signalling activated RhoA, resulting in enhanced SM α-actin transcription and filament polymerization [10]. PDGFRα phosphorylation activates RhoA which, through Rho-associated kinase (ROCK)-dependent cofilin phosphorylation and myosin light chain kinase-dependent pathways, enhances SM α-actin filament polymerization. In contrast, PDGFRβ signalling inhibits SM α-actin filaments by up-regulating RhoE, which inhibits ROCK and by PDGF-BB induced cofilin-mediated filament destabilization [10]. Thus the cell surface PDGFRα : PDGFRβ ratio and ligand concentration are critical determinants for commitment to a vascular SMC fate. A diagram showing PDGF receptor regulation of SM α-actin filament polymerization in MSCs, is shown in Figure 3.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: UK Centre for Tissue Engineering, Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, The University of Manchester, Manchester, UK.

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.

Show MeSH
Related in: MedlinePlus