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Progenitor cells identified by PDGFR-alpha expression in the developing and diseased human heart.

ABSTRACT: Platelet-derived growth factors (PDGFs) and their tyrosine kinase receptors play instrumental roles in embryonic organogenesis and diseases of adult organs. In particular, platelet-derived growth factor receptor-alpha (PDGFR?) is expressed by multipotent cardiovascular progenitors in mouse and human embryonic stem cell systems. Although cardiac PDGFR? expression has been studied in multiple species, little is known about its expression in the human heart. Using immunofluorescence, we analyzed PDGFR? expression in both human fetal and diseased adult hearts, finding strong expression in the interstitial cells of the epicardium, myocardium, and endocardium, as well as the coronary smooth muscle. Only rare endothelial cells and cardiomyocytes expressed PDGFR?. This pattern was consistent for both the fetal and adult diseased hearts, although more PDGFR?+ cardiomyocytes were noted in the latter. In vitro differentiation assays were then performed on the PDGFR?+ cell fraction isolated from the cardiomyocyte-depleted human fetal hearts. Protocols previously reported to direct differentiation to a cardiomyocyte (5-azacytidine), smooth muscle (PDGF-BB), or endothelial cell fates (vascular endothelial growth factor [VEGF]) were used. Although no significant cardiomyocyte differentiation was observed, PDGFR?+ cells generated significant numbers of smooth muscle cells (smooth muscle-?-actin+ and smooth muscle myosin+) and endothelial cells (CD31+). These data suggest that a subfraction of the cardiac PDGFR?+ populations are progenitors contributing predominantly to the vascular and mesenchymal compartments of the human heart. It may be possible to control the fate of these progenitors to promote vascularization or limit fibrosis in the injured heart.

SUBMITTER: Chong JJ

PROVIDER: S-EPMC3685392 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Progenitor cells identified by PDGFR-alpha expression in the developing and diseased human heart.

Chong James J H JJ Reinecke Hans H Iwata Mineo M Torok-Storb Beverly B Stempien-Otero April A Murry Charles E CE

Stem cells and development 20130326 13

Platelet-derived growth factors (PDGFs) and their tyrosine kinase receptors play instrumental roles in embryonic organogenesis and diseases of adult organs. In particular, platelet-derived growth factor receptor-alpha (PDGFRα) is expressed by multipotent cardiovascular progenitors in mouse and human embryonic stem cell systems. Although cardiac PDGFRα expression has been studied in multiple species, little is known about its expression in the human heart. Using immunofluorescence, we analyzed PD ...[more]

PMID: 23391309

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Project description:Glioma, the most prevalent malignancy in brain, is classified into four grades (I, II, III, and IV), and grade IV glioma is also known as glioblastoma multiforme (GBM). Aberrant activation of receptor tyrosine kinases (RTKs), including platelet-derived growth factor receptor (PDGFR), are frequently observed in glioma. Accumulating evidence suggests that PDGFR plays critical roles during glioma development and progression and is a promising drug target for GBM therapy. However, PDGFR inhibitor (PDGFRi) has failed in clinical trials, at least partially, due to the activation of other RTKs, which compensates for PDGFR inhibition and renders tumor cells resistance to PDGFRi. Therefore, identifying the RTKs responsible for PDGFRi resistance might provide new therapeutic targets to synergetically enhance the efficacy of PDGFRi. In this study, we analyzed the TCGA glioma database and found that the mRNA expressions of three RTKs, i.e. ERBB3, IGF1R, and TGFBR2, were positively correlated with that of PDGFR. Co-immunoprecipitation assay indicated novel interactions between the three RTKs and PDGFR in GBM cells. Moreover, concurrent expression of PDGFR with ERBB3, IGF1R, or TGFBR2 in GBM cells attenuated the toxicity of PDGFRi and maintained the activation of PDGFR downstream targets under the existence of PDGFRi. Thus, ERBB3, IGF1R, and TGFBR2 might participate in PDGFRi resistance of GBM cells. Consistent with this notion, combination of PDGFRi with inhibitor targeting either ERBB3 or IGF1R more potently suppressed the growth of GBM cells than each inhibitor alone. The positive correlations of PDGFR with ERBB3, IGF1R, and TGFBR2 were further confirmed in 66 GBM patient samples. Intriguingly, survival analysis showed that ERBB3 predicted poor prognosis in GBM patients with high PDGFRA expression. Altogether, our work herein suggested that ERBB3, IGF1R, and TGFBR2 were responsible for PDGFRi resistance and revealed that ERBB3 acted as potential prognostic marker and therapeutic target for GBM with high PDGFRA expression.

Dataset Information

Progenitor cells identified by PDGFR-alpha expression in the developing and diseased human heart.

Publications

Progenitor cells identified by PDGFR-alpha expression in the developing and diseased human heart.

Similar Datasets

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