| Popis: |
Background Bone marrow derived endothelial progenitor cells (EPCs) are immature endothelial cells (ECs) involved in neo-angiogenesis and endothelial homeostasis and are considered as a circulating reservoir for endothelial repair. Many studies showed that EPCs from patients with hematological and cardiovascular pathologies are impaired and insufficient; hence, allogenic sources from adult or cord blood are considered as good options for cell therapy applications. However, allogenic condition increases the chance of immune rejection, especially by T cells, before exerting the desired regenerative functions. TNFα is one of the main mediators of EPC activation that recognizes two distinct receptors. TNFR1 has ubiquitous expression and its interaction with TNFα leads to deleterious effects and apoptosis, whereas, TNFR2 is expressed on few cell types and is involved in protective and survival mechanisms. We have recently reported that human EPCs are immunosuppressive and this effect was TNFα-TNFR2 dependent. Here, we aimed to investigate if an adequate TNFα pre-conditioning could increase TNFR2 expression and prime EPCs towards more immunoregulatroy functions. Methods EPCs were pre-treated with several doses of TNFα to find the proper dose to up-regulate TNFR2 while keeping TNFR1 stable. Then, co-cultures of human EPCs and T cells were performed to assess if EPC immunoregulatory effect is increased. Results Treating EPCs with 1 ng/ml TNFα significantly up-regulated TNFR2 expression without unrestrained increase of TNFR1 and other endothelial injury markers. Moreover, TNFα priming through its interaction with TNFR2 remarkably enhanced EPC immunosuppressive and anti-inflammatory effects. Conversely, TNFα-TNFR1 interaction polarized EPCs towards pro-inflammatory and immunogenic functions. Conclusions We report for the first time the crucial role of inflammation, notably, the implication of TNFα-TNFR2 axis to boost EPC immunoregulatory functions. Priming EPCs with proper dose of TNFα prior to administration could provide a more protective immunosuppressive microenvironment and longer lasting cells which eventually lead to their better contribution to hematopoietic and vascular regeneration. |
