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Targeting the endothelial progenitor cell surface proteome to identify novel mechanisms that mediate angiogenic efficacy in a rodent model of vascular disease.

ABSTRACT: Endothelial progenitor cells (EPCs) promote angiogenesis, and clinical trials suggest autologous EPC-based therapy may be effective in treatment of vascular diseases. Albeit promising, variability in the efficacy of EPCs associated with underlying disease states has hindered the realization of EPC-based therapy. Here we first identify and characterize EPC dysfunction in a rodent model of vascular disease (SS/Mcwi rat) that exhibits impaired angiogenesis. To identify molecular candidates that mediate the angiogenic potential of these cells, we performed a broad analysis of cell surface protein expression using chemical labeling combined with mass spectrometry. Analysis revealed EPCs derived from SS/Mcwi rats express significantly more type 2 low-affinity immunoglobulin Fc-gamma (FCGR2) and natural killer 2B4 (CD244) receptors compared with controls. Genome-wide sequencing (RNA-seq) and qt-PCR confirmed isoforms of CD244 and FCGR2a transcripts were increased in SS/Mcwi EPCs. EPCs with elevated expression of FCGR2a and CD244 receptors are predicted to increase the probability of SS/Mcwi EPCs being targeted for death, providing a mechanistic explanation for their reduced angiogenic efficacy in vivo. Pathway analysis supported this contention, as "key" molecules annotated to cell death paths were differentially expressed in the SS/Mcwi EPCs. We speculate that screening and neutralization of cell surface proteins that "tag" and impair EPC function may provide an alternative approach to utilizing incompetent EPCs in greater numbers, as circulating EPCs are depleted in patients with vascular disease. Overall, novel methods to identify putative targets for repair of EPCs using discovery-based technologies will likely provide a major advance in the field of regenerative medicine.

SUBMITTER: Kaczorowski CC

PROVIDER: S-EPMC3841789 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Targeting the endothelial progenitor cell surface proteome to identify novel mechanisms that mediate angiogenic efficacy in a rodent model of vascular disease.

Kaczorowski Catherine C CC Stodola Timothy J TJ Hoffmann Brian R BR Prisco Anthony R AR Liu Pengyuan Y PY Didier Daniela N DN Karcher Jamie R JR Liang Mingyu M Jacob Howard J HJ Greene Andrew S AS

Physiological genomics 20130910 21

Endothelial progenitor cells (EPCs) promote angiogenesis, and clinical trials suggest autologous EPC-based therapy may be effective in treatment of vascular diseases. Albeit promising, variability in the efficacy of EPCs associated with underlying disease states has hindered the realization of EPC-based therapy. Here we first identify and characterize EPC dysfunction in a rodent model of vascular disease (SS/Mcwi rat) that exhibits impaired angiogenesis. To identify molecular candidates that med ...[more]

PMID: 24022221

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Project description:This study aimed to analyze the role of endothelial progenitor cell (EPC)-derived angiogenic factors and chemokines in the multistep process driving angiogenesis with a focus on the recently discovered macrophage migration inhibitory factor (MIF)/chemokine receptor axis. Primary murine and murine embryonic EPCs (eEPCs) were analyzed for the expression of angiogenic/chemokines and components of the MIF/CXC chemokine receptor axis, focusing on the influence of hypoxic versus normoxic stimulation. Hypoxia induced an upregulation of CXCR2 and CXCR4 but not CD74 on EPCs and triggered the secretion of CXCL12, CXCL1, MIF, and vascular endothelial growth factor (VEGF). These factors stimulated the transmigration activity and adhesive capacity of EPCs, with MIF and VEGF exhibiting the strongest effects under hypoxia. MIF-, VEGF-, CXCL12-, and CXCL1-stimulated EPCs enhanced tube formation, with MIF and VEGF exhibiting again the strongest effect following hypoxia. Tube formation following in vivo implantation utilizing angiogenic factor-loaded Matrigel plugs was only promoted by VEGF. Coloading of plugs with eEPCs led to enhanced tube formation only by CXCL12, whereas MIF was the only factor which induced differentiation towards an endothelial and smooth muscle cell (SMC) phenotype, indicating an angiogenic and differentiation capacity in vivo. Surprisingly, CXCL12, a chemoattractant for smooth muscle progenitor cells, inhibited SMC differentiation. We have identified a role for EPC-derived proangiogenic MIF, VEGF and MIF receptors in EPC recruitment following hypoxia, EPC differentiation and subsequent tube and vessel formation, whereas CXCL12, a mediator of early EPC recruitment, does not contribute to the remodeling process. By discerning the contributions of key angiogenic chemokines and EPCs, these findings offer valuable mechanistic insight into mouse models of angiogenesis and help to define the intricate interplay between EPC-derived angiogenic cargo factors, EPCs, and the angiogenic target tissue.

Dataset Information

Targeting the endothelial progenitor cell surface proteome to identify novel mechanisms that mediate angiogenic efficacy in a rodent model of vascular disease.

Publications

Targeting the endothelial progenitor cell surface proteome to identify novel mechanisms that mediate angiogenic efficacy in a rodent model of vascular disease.

Similar Datasets

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