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.

Human cardiac progenitor cell activation and regeneration mechanisms: exploring a novel myocardial ischemia/reperfusion in vitro model

“…CXCL6 is described as being an angiogenic chemokine secreted by CPCs [21]. In order to access if the I/R conditioned medium has a pro-angiogenic paracrine profile, the in vitro tube formation assay was performed.…”

“…The hCPCs employed in this work are not the same population involved in this controversy and were isolated and cultured using a different protocol (Patent WO2014141220A1), which was also used for the isolation of the hCPC population recently evaluated for the allogeneic treatment of AMI in CAREMI clinical trial (NCT02439398). Importantly, these cells were already extensively characterized at the immunomodulatory [14–17], total proteome [18], membrane proteome [19, 20], and secretome [21] levels. The regenerative benefit of these cells was studied in vivo in pig AMI animal model [22, 23].…”

Inflammatory Markers in Suction Blister Fluid: A Comparative Study Between Interstitial Fluid and Plasma

“…CXCL5 is secreted by endothelial cells in response to infection to recruit neutrophils (32). CXCL5 (33) and CXCL6 (34) are shown to have important paracrine functions, including regulation of gene expression and signaling for cell migration and angiogenesis. Our results confirm previous studies that the proteome of ISF is distinct from that of plasma.…”

Cardiac Progenitor Cells in Basic Biology and Regenerative Medicine

“…Interestingly, the latest report has revealed that majority (≈90%) of the resident c-kit + cells in the rodent heart are blood/endothelial lineage-committed cells, while cardiac c-kit + (blood/endothelial lineage-negative) cells represent ≤ 10% of the total c-kit + cells in the heart [ 29 ]. It is speculated that the positive effects seen from the delivered c-kit + cells in the post-MI setting could be due to the release of signaling molecules, rather than the engrafted cells themselves [ 30 , 31 ].…”