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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

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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fig02: 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.

Mentions: A reduction in oxygen level (hypoxia) has also been shown to induce murine MSCs to form in vitro capillary-like structures [75]. Our studies have also demonstrated human MSCs have an inherent capacity to rapidly form in vitro capillary-like structures, when cultured on three-dimensional matrigels or fibrin gels, under either normoxic or hypoxic conditions, as shown in Figure 2. Human MSCs co-cultured with mature endothelial cells also differentiated towards endothelial-like cells, which were inhibited using VEGF antisera [73], highlighting the principal role of VEGF in this differentiation event. While these studies clearly demonstrate that VEGF can stimulate VEGF receptor-negative MSCs, inducing differentiation towards endothelial cells, the mechanism has not been defined, but may well involve VEGF induced PDGF receptor signalling. Our studies using VEGF receptor-negative MSCs, demonstrated that 5 hrs VEGF-A stimulation did not induce VEGF receptor transcript expression [9], indicating a more sustained exposure is required to induce differentiation towards an endothelial fate. Thus, the role of VEGF-A induced PDGF receptor activation and signalling in directing MSC differentiation to endothelial cells requires further investigation.


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)

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.
© Copyright Policy
Related In: Results  -  Collection

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

fig02: 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.
Mentions: A reduction in oxygen level (hypoxia) has also been shown to induce murine MSCs to form in vitro capillary-like structures [75]. Our studies have also demonstrated human MSCs have an inherent capacity to rapidly form in vitro capillary-like structures, when cultured on three-dimensional matrigels or fibrin gels, under either normoxic or hypoxic conditions, as shown in Figure 2. Human MSCs co-cultured with mature endothelial cells also differentiated towards endothelial-like cells, which were inhibited using VEGF antisera [73], highlighting the principal role of VEGF in this differentiation event. While these studies clearly demonstrate that VEGF can stimulate VEGF receptor-negative MSCs, inducing differentiation towards endothelial cells, the mechanism has not been defined, but may well involve VEGF induced PDGF receptor signalling. Our studies using VEGF receptor-negative MSCs, demonstrated that 5 hrs VEGF-A stimulation did not induce VEGF receptor transcript expression [9], indicating a more sustained exposure is required to induce differentiation towards an endothelial fate. Thus, the role of VEGF-A induced PDGF receptor activation and signalling in directing MSC differentiation to endothelial cells requires further investigation.

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