Human mesenchymal stem cell-replicative senescence and oxidative stress are closely linked to aneuploidy

In most clinical trials, human mesenchymal stem cells (hMSCs) are expanded in vitro before implantation. The genetic stability of human stem cells is critical for their clinical use. However, the relationship between stem-cell expansion and genetic stability is poorly understood. Here, we demonstrate that within the normal expansion period, hMSC cultures show a high percentage of aneuploid cells that progressively increases until senescence. Despite this accumulation, we show that in a heterogeneous culture the senescence-prone hMSC subpopulation has a lower proliferation potential and a higher incidence of aneuploidy than the non-senescent subpopulation. We further show that senescence is linked to a novel transcriptional signature that includes a set of genes implicated in ploidy control. Overexpression of the telomerase catalytic subunit (human telomerase reverse transcriptase, hTERT) inhibited senescence, markedly reducing the levels of aneuploidy and preventing the dysregulation of ploidy-controlling genes. hMSC-replicative senescence was accompanied by an increase in oxygen consumption rate (OCR) and oxidative stress, but in long-term cultures that overexpress hTERT, these parameters were maintained at basal levels, comparable to unmodified hMSCs at initial passages. We therefore propose that hTERT contributes to genetic stability through its classical telomere maintenance function and also by reducing the levels of oxidative stress, possibly, by controlling mitochondrial physiology. Finally, we propose that aneuploidy is a relevant factor in the induction of senescence and should be assessed in hMSCs before their clinical use.This work was supported by grants to AB from the Ministry of Science and Innovation (SAF 2008-02099; PLE2009-0147 and PSE010000-2009-3), the Comunidad Autonoma de Madrid (P-BIO-0306-2006) and the Red de Terapia Celular del Instituto de Salud Carlos III (TerCel); to ES from the Fundacion Mutua Madrilena, the Ministry of Education (Ramon y Cajal program), the Ministry of Health (FIS PI071023); and to ER from Instituto de Salud Carlos III-FEDER (PS09/01093) and Fundacion Salud 2000-Merck Serono. JCE is a predoctoral fellow funded by TerCel. The CNIC is supported by the Ministry of Economy and Competitiveness and the Pro-CNIC Foundation.S

Immunomodulation and Anti-Inflammatory Effects of Garlic Compounds

CONACYT [295457, 170901]; Universidad de Guadalajara [222769-PROSNI-2014

Antioxidant Supplementation modulates neutrophil inflammatory response to exercise-induced stress.

[eng] The aim of the present report was to evaluate the inflammatory response to a 2000-m running test considering neutrophil myeloperoxidase as an inflammatory marker, and to verify if supplements rich in antioxidants could modulate Post-test antioxidant and anti-inflammatory responses. To this end, a 21-day homogenization period was carried out with three groups: a control group, a supplemented group taking an almond beverage enriched with vitamins C and E and a third group consuming the same beverage but enriched with Lippia citriodora extract. At the end of this period, participants performed a 2000-m run, and blood samples were obtained the day before and immediately after the running test. Plasma and neutrophils were isolated. As a result, plasma creatine kinase and myoglobin increased, indicating Post-test muscle damage. Plasma oxidative markers were increased in all groups, except in the group supplemented with the almond beverage. Neutrophil antioxidant enzymes were significantly increased only in the control group, suggesting an antioxidant effect of the supplements provided in the other groups. Myeloperoxidase activity was significantly increased after the test in the control group, while increased enzyme levels were detected in plasma of the supplement groups. Therefore, antioxidant consumption seems to favour myeloperoxidase release. The connection of this observation with post-exercise recovery will require further investigation