Abstract
Studies in recent years have established that the principal effects in cardiac cell therapy are associated with paracrine/autocrine factors. We combined several complementary techniques to define human cardiac progenitor cell (CPC) secretome constituted by 914 proteins/genes; 51% of these are associated with the exosomal compartment. To define the set of proteins specifically or highly differentially secreted by CPC, we compared human mesenchymal stem cells and dermal fibroblasts; the study defined a group of growth factors, cytokines and chemokines expressed at high to medium levels by CPC. Among them, IL-1, GROa (CXCL1), CXCL6 (GCP2) and IL-8 are examples whose expression was confirmed by most techniques used. ELISA showed that CXCL6 is significantly overexpressed in CPC conditioned medium (CM) (18- to 26-fold) and western blot confirmed expression of its receptors CXCR1 and CXCR2. Addition of anti-CXCL6 completely abolished migration in CPC-CM compared with anti-CXCR2, which promoted partial inhibition, and anti-CXCR1, which was inefficient. Anti-CXCL6 also significantly inhibited CPC CM angiogenic activity. In vivo evaluation also supported a relevant role for angiogenesis. Altogether, these results suggest a notable angiogenic potential in CPC-CM and identify CXCL6 as an important paracrine factor for CPC that signals mainly through CXCR2.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Neutralizing / pharmacology
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Cell Movement
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Chemokine CXCL1 / genetics
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Chemokine CXCL1 / metabolism
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Chemokine CXCL6 / antagonists & inhibitors
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Chemokine CXCL6 / genetics*
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Chemokine CXCL6 / metabolism
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Culture Media, Conditioned / chemistry
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Culture Media, Conditioned / metabolism
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Gene Expression Regulation
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Human Umbilical Vein Endothelial Cells / cytology
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Interleukin-1 / genetics
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Interleukin-1 / metabolism
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Interleukin-8 / genetics
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Interleukin-8 / metabolism
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Male
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Mesenchymal Stem Cells / cytology
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Mesenchymal Stem Cells / drug effects
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Mesenchymal Stem Cells / metabolism
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Mice
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Mice, Inbred C57BL
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Myocardium / cytology
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Myocardium / metabolism*
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Neovascularization, Physiologic / genetics*
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Paracrine Communication / genetics*
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Proteome / genetics*
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Proteome / metabolism
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Receptors, Interleukin-8A / antagonists & inhibitors
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Receptors, Interleukin-8A / genetics
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Receptors, Interleukin-8A / metabolism
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Receptors, Interleukin-8B / antagonists & inhibitors
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Receptors, Interleukin-8B / genetics
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Receptors, Interleukin-8B / metabolism*
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Signal Transduction
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Stem Cells / cytology
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Stem Cells / drug effects
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Stem Cells / metabolism*
Substances
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Antibodies, Neutralizing
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CXCL1 protein, human
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CXCL6 protein, human
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CXCR2 protein, human
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Chemokine CXCL1
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Chemokine CXCL6
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Culture Media, Conditioned
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Interleukin-1
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Interleukin-8
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Proteome
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Receptors, Interleukin-8A
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Receptors, Interleukin-8B