TWEAK promotes endothelial progenitor cell vasculogenesis to alleviate acute myocardial infarction via the Fn14‑NF‑κB signaling pathway

Abstract

Acute myocardial infarction (AMI) remains one of the leading causes of mortality worldwide; however, endothelial progenitor cell (EPC) transplantation has been proposed as a promising treatment strategy for EPC. High levels of tumor necrosis factor-related weak inducer of apoptosis (TWEAK) have been reported in AMI, although its effect on EPCs has not been reported. In the present study, immunofluorescence and flow cytometry were performed to assess the effect of TWEAK in isolated mouse EPCs. Echocardiography was used to evaluate the cardiac function of murine hearts following EPC treatment in the AMI model, while collagen synthesis within the heart tissue was assessed using Masson's trichrome staining. A tube formation assay and Transwell migration assay were performed to investigate the effects of TWEAK on vessel formation and EPC migration in vitro. Angiogenesis and arteriogenesis were assessed in vivo using immunohistochemistry and western blotting was performed to determine the effect of TWEAK-mediated nuclear factor (NF)-κB pathway activation in EPCs. The results revealed that TWEAK promotes EPC migration, tube formation and viability in vitro. Furthermore, TWEAK treatment resulted in improved cardiac function, decreased heart collagen and vasculogenesis in mice with AMI, which was mediated by the TWEAK- fibroblast growth factor-inducible 14 (Fn14)-NF-κB signaling pathway, as determined using Fn14 small interfering (si)RNA and Bay 11–7082 (an NF-κB inhibitor). In summary, the results of the present study suggest that activation of the TWEAK-Fn14-NF-κB signaling pathway exerts a beneficial effect on EPCs for the treatment of AMI.

The TWEAK/Fn14/CD163 axis—implications for metabolic disease

“…Similar to atherosclerosis, plasma sTWEAK expression is significantly higher in patients who suffered from AMI. However, in this instance, TWEAK encourages beneficial endothelial progenitor cell (EPC) vasculogenic properties to relieve acute myocardial infarction via the Fn14‑NF‑κB signalling pathway and additionally increases the migration of EPC to the site of injury [ 106 ]. Although not directly related to cardiovascular disease (CVD), it is worth mentioning that TWEAK/Fn14 activation has been shown to induce beneficial migration and cytokine production of both dermal microvascular endothelial cells and dermal fibroblasts in burn wounds [ 46 ].…”

Hepatic progenitor cell activation is induced by the depletion of the gut microbiome in mice

“…TWEAK is a cytokine produced by macrophages, belongs to the TNF superfamily and may regulate inflammation, cell apoptosis, and proliferation. TWEAK has been shown to be associated with HPC activation in previous studies (Akahori et al, ; Hamill, Michaelson, Hahm, Burkly, & Kessler, ; Sheng et al, ). The mRNA expression of Tweak was significantly higher in the Abx mice than it was in the control mice (Figure d, p < 0.0001).…”

A potential fate decision landscape of the TWEAK/Fn14 axis on stem and progenitor cells: a systematic review

“…Therefore, EPCs have been postulated as valuable cellular candidates or therapeutic targets to improve cardiovascular disease, such as acute myocardial infarction (AMI). TWEAK is significantly escalated in patients and mice with AMI compared to healthy controls [ 37 , 38 ]. Transplantation of TWEAK-pretreated EPCs into AMI mice significantly improved cardiac function, alleviated AMI, and facilitated the differentiation of EPCs to form vessels [ 38 ].…”