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PDGFRbeta+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival.

ABSTRACT: The microvasculature consists of endothelial cells and their surrounding pericytes. Few studies on the regulatory mechanisms of tumour angiogenesis have focused on pericytes. Here we report the identification of tumour-derived PDGFRbeta (+) (platelet-derived growth factor receptor beta) progenitor perivascular cells (PPCs) that have the ability to differentiate into pericytes and regulate vessel stability and vascular survival in tumours. A subset of PDGFRbeta (+) PPCs is recruited from bone marrow to perivascular sites in tumours. Specific inhibition of PDGFRbeta signalling eliminates PDGFRbeta (+) PPCs and mature pericytes around tumour vessels, leading to vascular hyperdilation and endothelial cell apoptosis in pancreatic islet tumours of transgenic Rip1Tag2 mice.

SUBMITTER: Song S

PROVIDER: S-EPMC2771163 | biostudies-literature | 2005 Sep

REPOSITORIES: biostudies-literature

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PDGFRbeta+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival.

Song Steven S Ewald Andrew J AJ Stallcup William W Werb Zena Z Bergers Gabriele G

Nature cell biology 20050821 9

The microvasculature consists of endothelial cells and their surrounding pericytes. Few studies on the regulatory mechanisms of tumour angiogenesis have focused on pericytes. Here we report the identification of tumour-derived PDGFRbeta (+) (platelet-derived growth factor receptor beta) progenitor perivascular cells (PPCs) that have the ability to differentiate into pericytes and regulate vessel stability and vascular survival in tumours. A subset of PDGFRbeta (+) PPCs is recruited from bone mar ...[more]

PMID: 16113679

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Project description:Vascular calcification is an advanced feature of atherosclerosis for which no effective therapy is available. To investigate the modulation or reversal of calcification, we identified calcifying progenitor cells and investigated their calcifying/decalcifying potentials. Cells from the aortas of mice were sorted into four groups using Sca-1 and PDGFR? markers. Sca-1(+) (Sca-1(+)/PDGFR?(+) and Sca-1(+)/PDGFR?(-)) progenitor cells exhibited greater osteoblastic differentiation potentials than Sca-1(-) (Sca-1(-)/PDGFR?(+) and Sca-1(-)/PDGFR?(-)) progenitor cells. Among Sca-1(+) progenitor populations, Sca-1(+)/PDGFR?(-) cells possessed bidirectional differentiation potentials towards both osteoblastic and osteoclastic lineages, whereas Sca-1(+)/PDGFR?(+) cells differentiated into an osteoblastic lineage unidirectionally. When treated with a peroxisome proliferator activated receptor ? (PPAR?) agonist, Sca-1(+)/PDGFR?(-) cells preferentially differentiated into osteoclast-like cells. Sca-1(+) progenitor cells in the artery originated from the bone marrow (BM) and could be clonally expanded. Vessel-resident BM-derived Sca-1(+) calcifying progenitor cells displayed nonhematopoietic, mesenchymal characteristics. To evaluate the modulation of in vivo calcification, we established models of ectopic and atherosclerotic calcification. Computed tomography indicated that Sca-1(+) progenitor cells increased the volume and calcium scores of ectopic calcification. However, Sca-1(+)/PDGFR?(-) cells treated with a PPAR? agonist decreased bone formation 2-fold compared with untreated cells. Systemic infusion of Sca-1(+)/PDGFR?(-) cells into Apoe(-/-) mice increased the severity of calcified atherosclerotic plaques. However, Sca-1(+)/PDGFR?(-) cells in which PPAR? was activated displayed markedly decreased plaque severity. Immunofluorescent staining indicated that Sca-1(+)/PDGFR?(-) cells mainly expressed osteocalcin; however, activation of PPAR? triggered receptor activator for nuclear factor-?B (RANK) expression, indicating their bidirectional fate in vivo. These findings suggest that a subtype of BM-derived and vessel-resident progenitor cells offer a therapeutic target for the prevention of vascular calcification and that PPAR? activation may be an option to reverse calcification.

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PDGFRbeta+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival.

Publications

PDGFRbeta+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival.

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