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CXCL6 is an important paracrine factor in the pro-angiogenic human cardiac progenitor-like cell secretome.

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.

SUBMITTER: Toran JL

PROVIDER: S-EPMC5624898 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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CXCL6 is an important paracrine factor in the pro-angiogenic human cardiac progenitor-like cell secretome.

Torán José Luis JL Aguilar Susana S López Juan Antonio JA Torroja Carlos C Quintana Juan Antonio JA Santiago Cesar C Abad José Luis JL Gomes-Alves Patricia P Gonzalez Andrés A Bernal Juan Antonio JA Jiménez-Borreguero Luis Jesús LJ Alves Paula Marques PM R-Borlado Luis L Vázquez Jesús J Bernad Antonio A

Scientific reports 20171002 1

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 defi ...[more]

PMID: 28970523

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Project description:Tissue (re)vascularization strategies face various challenges, as therapeutic cells do not survive long enough in situ, while the administration of pro-angiogenic factors is hampered by fast clearance and insufficient ability to emulate complex spatiotemporal signaling. Here, we propose to address these limitations by engineering a functional biomaterial capable of capturing and concentrating the pro-angiogenic activities of mesenchymal stem cells (MSCs). In particular, dextran sulfate, a high molecular weight sulfated glucose polymer, supplemented to MSC cultures, interacts with MSC-derived extracellular matrix (ECM) components and facilitates their co-assembly and accumulation in the pericellular space. Upon decellularization, the resulting dextran sulfate-ECM hybrid material can be processed into MIcroparticles of SOlidified Secretome (MIPSOS). The insoluble format of MIPSOS protects protein components from degradation, while facilitating their sustained release. Proteomic analysis demonstrates that MIPSOS are highly enriched in pro-angiogenic factors, resulting in an enhanced pro-angiogenic bioactivity when compared to naïve MSC-derived ECM (cECM). Consequently, intravital microscopy of full-thickness skin wounds treated with MIPSOS demonstrates accelerated revascularization and healing, far superior to the therapeutic potential of cECM. Hence, the microparticle-based solidified stem cell secretome provides a promising platform to address major limitations of current therapeutic angiogenesis approaches. Graphical abstract A high molecular weight sulfated polyglucose polymer, dextran sulfate, co-assembles with mesenchymal stem cell derived secretome into insoluble microparticles (named MIPSOS). Simultaneously, dextran sulfate's ability to mimic heparan sulfate promotes the accumulation of a plethora of pro-angiogenic factors, resulting in superior pro-angiogenic properties and thus therapeutic potential.Image 1 Highlights • Dextran sulfate assembles with mesenchymal stem cell secretome.• As a result, microparticles of solidified stem cell secretome (MIPSOS) are formed.• The insoluble MIPSOS format protects proteins from premature degradation.• MIPSOS are enriched in pro-angiogenic factors and exhibit gradual release kinetics.• MIPSOS demonstrate superior pro-angiogenic properties and thus therapeutic potential.

Project description:RationaleCardiac progenitor cells are an attractive cell type for tissue regeneration, but their mechanism for myocardial remodeling is still unclear.ObjectiveThis investigation determines how chronological age influences the phenotypic characteristics and the secretome of human cardiac progenitor cells (CPCs), and their potential to recover injured myocardium.Methods and resultsAdult (aCPCs) and neonatal (nCPCs) cells were derived from patients aged >40 years or <1 month, respectively, and their functional potential was determined in a rodent myocardial infarction model. A more robust in vitro proliferative capacity of nCPCs, compared with aCPCs, correlated with significantly greater myocardial recovery mediated by nCPCs in vivo. Strikingly, a single injection of nCPC-derived total conditioned media was significantly more effective than nCPCs, aCPC-derived TCM, or nCPC-derived exosomes in recovering cardiac function, stimulating neovascularization, and promoting myocardial remodeling. High-resolution accurate mass spectrometry with reverse phase liquid chromatography fractionation and mass spectrometry was used to identify proteins in the secretome of aCPCs and nCPCs, and the literature-based networking software identified specific pathways affected by the secretome of CPCs in the setting of myocardial infarction. Examining the TCM, we quantified changes in the expression pattern of 804 proteins in nCPC-derived TCM and 513 proteins in aCPC-derived TCM. The literature-based proteomic network analysis identified that 46 and 6 canonical signaling pathways were significantly targeted by nCPC-derived TCM and aCPC-derived TCM, respectively. One leading candidate pathway is heat-shock factor-1, potentially affecting 8 identified pathways for nCPC-derived TCM but none for aCPC-derived TCM. To validate this prediction, we demonstrated that the modulation of heat-shock factor-1 by knockdown in nCPCs or overexpression in aCPCs significantly altered the quality of their secretome.ConclusionsA deep proteomic analysis revealed both detailed and global mechanisms underlying the chronological age-based differences in the ability of CPCs to promote myocardial recovery via the components of their secretome.

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CXCL6 is an important paracrine factor in the pro-angiogenic human cardiac progenitor-like cell secretome.

Publications

CXCL6 is an important paracrine factor in the pro-angiogenic human cardiac progenitor-like cell secretome.

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