Tumor Necrosis Factor α Regulates Endothelial Progenitor Cell Migration via CADM1 and NF-kB

Abstract

Shortly after the discovery of endothelial progenitor cells (EPCs) in 1997, many clinical trials were conducted using EPCs as a cellular based therapy with the goal of restoring damaged organ function by inducing growth of new blood vessels (angiogenesis). Results were disappointing, largely because the cellular and molecular mechanisms of EPC-induced angiogenesis were not clearly understood. Following injection, EPCs must migrate to the target tissue and engraft prior to induction of angiogenesis. In this study EPC migration was investigated in response to tumor necrosis factor α (TNFα), a pro-inflammatory cytokine, to test the hypothesis that organ damage observed in ischemic diseases induces an inflammatory signal that is important for EPC homing. In this study, EPC migration and incorporation were modeled in vitro using a co-culture assay where TNFα treated EPCs were tracked while migrating towards vessel-like structures. It was found that TNFα treatment of EPCs increased migration and incorporation into vessel-like structures. Using a combination of genomic and proteomic approaches, NF-kB mediated upregulation of CADM1 was identified as a mechanism of TNFα induced migration. Inhibition of NF-kB or CADM1 significantly decreased migration of EPCs in vitro suggesting a role for TNFα signaling in EPC homing during tissue repair.

Regulatory mechanisms of Robo4 and their effects on angiogenesis

“…Activation of NF-kB in inflammatory cells in response to infectious agents, inflammatory cytokines and necrotic cell products leads to the release of inflammatory, angiogenic, growth and survival factors in tumor tissues [83]. Tumor necrosis factor α (TNFα) increases the migration and incorporation of endothelial progenitor cells (EPCs) into vessel-like structures through NF-kB-mediated up-regulation of CADM1, indicating that NF-kB might modulate the functions of ECs by regulating the expression of related genes under inflammatory conditions [84]. According to Tanaka et al [58], TNFα increased Robo4 expression in mice and human primary ECs by activating NF-kB.…”

TNFα priming through its interaction with TNFR2 enhances Endothelial Progenitor Cell immunosuppressive effect: new hope for their widespread clinical application

“…[27][28][29] In ammatory environment is essential for EC migration and angiogenic function. 30 Tumor necrosis factor alpha (TNFα) is a pro-in ammatory cytokine that could regulate both pro-and anti-angiogenic activities. [31][32][33] The concentration of TNFα and duration of exposure can control this dual effect.…”

Single-Cell Transcriptomic Profiling and Characterization of Endothelial Progenitor Cells: New Approach for Finding Novel Markers

“…The second group is implicated in ECs/EPCs-immune cells interaction, proliferation, migration, survival, apoptosis, angiogenesis, immunogenicity and immune-modulation. It includes TNF-α, TNFR2/P75, TNFR1/P55 and TRAIL (Tumor Necrosis Factor Related Apoptosis Inducing Ligand) [36][37][38][39][40]. The third group of factors is engaged in proliferation, survival, migration and differentiation of vascular stem/progenitor cells which includes closely-related cells co-enhabiting the vascular niche; namely they are EPCs, smooth muscle [43][44][45].…”