Elucidation of the molecular and bionergetic mechanisms underlying the resistance to oxidatives stress and the pro-recovery effect of H2O2- preconditioned adipose-derived stem cells

Abstract

In the field of regenerative medicine, it has been pointed out the relevance of human adipose derived stem cells (hASCs) for cell therapy. They can be easily obtained, have low immunogenicity, and secrete soluble factors that could regulate neuroinflammation and oxidative stress. However, their transplantation at the site of injury results in a low percentage of survival and engraftment, mainly due to the harsh microenvironment they encounter. To address this issue, it is imperative to pre-adapt cells, so that they resist harmful environmental factors such as oxidative stress. In this study, we preconditioned hASCs (PC-hASCs) with low doses of H2O2 and evaluated their resistance to an oxidative stress insult. PC-hASCs displayed lower levels of ROS, apoptosis and cytotoxicity than hASCs, indicating their increased capacity to resist to oxidative stress. In addition, we analyzed the molecular and bioenergetic mechanisms underlying the survival and adaptation of PC-hASCs under oxidative stress. On these conditions, PC-hASCs i, reduce intracellular ROS levels by overexpressing the transcription factor NRF2 and their related antioxidant enzymes HO-1, SOD-1, GPx-1, and CAT; ii, reduce the secretion of pro-inflammatory molecules COX-2 and IL-1ß by attenuating the expression of NF-kB, and iii, increase the total ATP production rate by adapting their metabolism in order to meet the bioenergetic demand required to survive. Finally, we evaluated the therapeutic role of PC-hASCs to overcome the deleterious effect of oxidative stress in an oligodendroglial cell population, and proved that PC-hASCs restored cell viability and diminished the intracellular ROS levels of these damaged oligodendrocytes by promoting their antioxidant response.Altogether, these findings support that PC-hASCs, given their beneficial advantages, might be considered an important breakthrough in cell¿based therapies.