TNFR1 signaling resistance associated with female stem cell cytokine production is independent of TNFR2-mediated pathways.
End-organ ischemia is a common source of patient morbidity and mortality. Stem cell therapy represents a novel treatment modality for ischemic diseases and may aid injured tissues through the release of beneficial paracrine mediators. Female bone marrow mesenchymal stem cells (MSCs) have demonstrated a relative resistance to detrimental TNF receptor 1 (TNFR1) signaling and are thought to be superior to male stem cells in limiting inflammation. However, it is not known whether sex differences exist in TNF receptor 2 (TNFR2)-ablated MSCs. Therefore, we hypothesized that 1) sex differences would be observed in wild-type (WT) and TNFR2-ablated MSC cytokine signaling, and 2) the production of IL-6, VEGF, and IGF-1 in males, but not females, would be mediated through TNFR2. MSCs were harvested from male and female WT and TNFR2 knockout (TNFR2KO) mice and were subsequently exposed to TNF (50 ng/ml) or LPS (100 ng/ml). After 24 h, supernatants were collected and measured for cytokines. TNF and LPS stimulated WT stem cells to produce cytokines, but sex differences were only seen in IL-6 and IGF-1 after TNF stimulation. Ablation of TNFR2 increased VEGF and IGF-1 production in males compared with wild-type, but no difference was observed in females. Female MSCs from TNFR2KOs produced significantly lower levels of VEGF and IGF-1 compared with male TNFR2KOs. The absence of TNFR2 signaling appears to play a greater role in male MSC cytokine production. As a result, male, but not female stem cell cytokine production may be mediated through TNFR2 signaling cascades.
Markel
Troy A
TA
Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Crisostomo
Paul R
PR
Wang
Meijing
M
Wang
Yue
Y
Lahm
Tim
T
Novotny
Nathan M
NM
Tan
Jiangning
J
Meldrum
Daniel R
DR
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000502:physiology*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000502:physiology*; D012737:Sex Factors; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D016207:Cytokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D007334:Insulin-Like Growth Factor I