Sex dimorphisms in activated mesenchymal stem cell function.
The plasticity of bone marrow-derived stem cells (BMSCs) has resulted in positive remodeling and the regeneration of viable tissues. However, BMSC release of growth factors, which limit apoptosis and inflammation, may play an important role in conferring organ protection. Recent studies also indicate that those patients with higher circulating BMSC counts may be more resistant to septic and traumatic insults. There are clear sex differences in response to such insults. Within the population of BMSC, mesenchymal stem cells (MSCs) may have clinical advantages. Therefore, we hypothesize that sex differences in the MSC paracrine response to acute injury exist. Mesenchymal stem cells were obtained from male and female mice. One million MSCs per well (triplicate wells per group) were stressed by hypoxia and increasing doses of endotoxin (lipopolysaccharide [LPS]) and hydrogen peroxide. Mesenchymal stem cell activation was determined by measuring vascular endothelial growth factor (VEGF) and tumor necrosis factor alpha production by enzyme-linked immunosorbent assay. Differences were considered significant if P < 0.05.


RESULTS
Lipopolysaccharide resulted in significant activation of both male and female MSCs. However, LPS provoked significantly more VEGF production in female MSCs versus male MSCs at all LPS doses. Hypoxia of 1 h and hydrogen pyroxide exposure also caused significantly more VEGF production in female MSCs versus male MSCs. Female MSCs expressed significantly less tumor necrosis factor alpha than male MSCs after acute LPS and hypoxia.


CONCLUSIONS
This study constitutes the first demonstration that sex differences exist in activated MSC function. Sex differences in progenitor cell function may have important implications in understanding the observed sex differences in the host's response to injury.
Crisostomo
Paul R
PR
Department of Surgery, Center for Immunobiology, Indiana University School of Medicine, 545 Barnhill Drive, Indianapolis, IN 46202, USA.
Wang
Meijing
M
Herring
Christine M
CM
Morrell
Eric D
ED
Seshadri
Preethi
P
Meldrum
Kirstan K
KK
Meldrum
Daniel R
DR
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D005260:Female; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012737:Sex Factors; D013234:Stem Cells / Q000166:cytology*; D017154:Stromal Cells / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D006861:Hydrogen Peroxide