Gender differences in injury induced mesenchymal stem cell apoptosis and VEGF, TNF, IL-6 expression: role of the 55 kDa TNF receptor (TNFR1)

J Mol Cell Cardiol. 2007 Jan;42(1):142-9. doi: 10.1016/j.yjmcc.2006.09.016. Epub 2006 Oct 30.


Concomitant pro- and anti-inflammatory properties of bone marrow stem cells (BMSC) may be an important aspect of their ability to heal injured tissue. However, very few studies have examined whether gender differences exist in BMSC function. Indeed, it remains unknown whether gender differences exist in BMSC function and ability to resist apoptosis, and if so, whether TNF receptor 1 (TNFR1) plays a role in these differences. We hypothesized that TNFR1 ablation equalizes gender differences in bone marrow mesenchymal stem cell (MSC) apoptosis, as well as expression of vascular endothelial growth factor (VEGF), TNF and interleukin (IL)-6. Mouse MSCs from male wild type (WT), female WT, male TNFR1 knockouts (TNFR1KO) and female TNFR1KO were stressed by endotoxin 200 ng/ml or 1 h hypoxia. MSC activation was determined by measuring VEGF, TNF and IL-6 production (ELISA). Differences considered significant if p<0.05. LPS and hypoxia resulted in significant activation in all experimental groups compared to controls. Male WT demonstrated significantly greater TNF and IL-6 and significantly less VEGF release than female WT MSCs. However, release of TNF, IL-6 and VEGF in male TNFR1 knockouts differed from male WT, but was not different from female WT MSCs. Similarly apoptosis in hypoxic male TNFRIKO differed from male WT, but it was not different from apoptosis from WT female. Female WT did not differ in TNF, IL-6 and VEGF release compared to female TNFR1KO. Gender differences exist in injury induced BMSC VEGF, TNF and IL-6 expression. TNFR1 may autoregulate VEGF, TNF and IL-6 expression in males more than females. MSCs are novel therapeutic agents for organ protection, but further study of the disparate expression of VEGF, TNF and IL-6 in males and females as well as the role of TNFR1 in these gender differences is necessary to maximize this protection.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Cell Hypoxia
  • Female
  • In Vitro Techniques
  • Interleukin-6 / metabolism*
  • Lipopolysaccharides / pharmacology
  • Male
  • Mesenchymal Stem Cell Transplantation
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Reperfusion Injury / therapy
  • Paracrine Communication
  • Receptors, Tumor Necrosis Factor, Type I / deficiency
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*
  • Sex Characteristics
  • Tumor Necrosis Factor-alpha / metabolism*
  • Vascular Endothelial Growth Factor A / metabolism*


  • Interleukin-6
  • Lipopolysaccharides
  • Receptors, Tumor Necrosis Factor, Type I
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse