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TNF? priming through its interaction with TNFR2 enhances endothelial progenitor cell immunosuppressive effect: new hope for their widespread clinical application.

ABSTRACT:

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 cardiovascular pathologies are impaired and insufficient; hence, allogenic sources of EPCs from adult or cord blood are considered as good choices for cell therapy applications. However, allogenic condition increases the chance of immune rejection, especially by T cells, before exerting the desired regenerative functions. TNF? is one of the main mediators of EPC activation that recognizes two distinct receptors, TNFR1 and TNFR2. We have recently reported that human EPCs are immunosuppressive and this effect was TNF?-TNFR2 dependent. Here, we aimed to investigate if an adequate TNF? pre-conditioning could increase TNFR2 expression and prime EPCs towards more immunoregulatory functions.

Methods

EPCs were pre-treated with several doses of TNF? to find the proper dose to up-regulate TNFR2 while keeping the TNFR1 expression stable. Then, co-cultures of human EPCs and human T cells were performed to assess whether TNF? priming would increase EPC immunosuppressive and immunomodulatory effect.

Results

Treating EPCs with 1 ng/ml TNF? significantly up-regulated TNFR2 expression without unrestrained increase of TNFR1 and other endothelial injury markers. Moreover, TNF? priming through its interaction with TNFR2 remarkably enhanced EPC immunosuppressive and anti-inflammatory effects. Conversely, blocking TNFR2 using anti-TNFR2 mAb followed by 1 ng/ml of TNF? treatment led to the TNF?-TNFR1 interaction and polarized EPCs towards pro-inflammatory and immunogenic functions.

Conclusions

We report for the first time the crucial impact of inflammation notably the TNF?-TNFR signaling pathway on EPC immunological function. Our work unveils the pro-inflammatory role of the TNF?-TNFR1 axis and, inversely the anti-inflammatory implication of the TNF?-TNFR2 axis in EPC immunoregulatory functions. Priming EPCs with 1 ng/ml of TNF? prior to their administration could boost them toward a more immunosuppressive phenotype. This could potentially lead to EPCs' longer presence in vivo after their allogenic administration resulting in their better contribution to angiogenesis and vascular regeneration. Video Abstract.

SUBMITTER: Nouri Barkestani M

PROVIDER: S-EPMC7784277 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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TNFα priming through its interaction with TNFR2 enhances endothelial progenitor cell immunosuppressive effect: new hope for their widespread clinical application.

Nouri Barkestani Mahsa M Shamdani Sara S Afshar Bakshloo Mazdak M Arouche Nassim N Bambai Bijan B Uzan Georges G Naserian Sina S

Cell communication and signaling : CCS 20210104 1

<h4>Background</h4>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 cardiovascular pathologies are impaired and insufficient; hence, allogenic sources of EPCs from adult or cord blood are considered as good choices for cell therapy applications. However, allogenic condition incre ...[more]

PMID: 33397378

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