Nrf-2 overexpression in mesenchymal stem cells reduces oxidative stress-induced apoptosis and cytotoxicity

Abstract

The most prominent capabilities of mesenchymal stem cells (MCSs) which make them promising for therapeutic applications are their capacity to endure and implant in the target tissue. However, the therapeutic applications of these cells are limited due to their early death within the first few days following transplantation. Therefore, to improve cell therapy efficacy, it is necessary to manipulate MSCs to resist severe stresses imposed by microenvironment. In this study, we manipulated MSCs to express a cytoprotective factor, nuclear factor erythroid-2 related factor 2 (Nrf2) to address this issue. Full-length human Nrf2 cDNA was isolated and TOPO cloned into TOPO cloning vector and then transferred to gateway adapted adenovirus expression vector by LR recombination reaction. Afterwards, the Nrf2 bearing recombinant virus was prepared in appropriate mammalian cell line and used to infect MSCs. The viability and apoptosis of the Nrf2 expressing MSCs were evaluated following hypoxic and oxidative stress conditions. Transient expression of Nrf2 by MSCs protected them against cell death and the apoptosis triggered by hypoxic and oxidative stress conditions. Nrf2 also enhanced the activity of SOD and HO-1. These findings could be used as a strategy for prevention of graft cell death in MSC-based cell therapy. It also indicates that management of cellular stress responses can be used for practical applications.

Activation of Liver X Receptor Improves Viability of Adipose-Derived Mesenchymal Stem Cells to Attenuate Myocardial Ischemia Injury Through TLR4/NF-κB and Keap-1/Nrf-2 Signaling Pathways

“…Our group also found that regulating local inflammation in ischemic tissue with sarpogrelate could enhance engrafted AD-MSCs viability and antiapoptotic/proangiogenic efficacy in vivo (7). In addition to microenvironmental regulation, increasing the stem cells' ability to resist local stress, such as local inflammation and oxidative stress, is also crucial for stem cell survival and efficacy (22,37). Therefore, it is imperative to improve the engraftment microenvironment as well as reinforce stem cell biological function to withstand the inhospitable ischemic milieu of the infarcted heart.…”

In vitro augmentation of mesenchymal stem cells viability in stressful microenvironments

“…Transient overexpression of nuclear factor related (erythroid-derived 2)-like 2 (Nrf2) in MSCs results in increased level of super oxide dismutase (SOD) and heme oxygenase-1 Akt a type of protein kinase; eNOS endogenous Nitric oxide synthesis (HO-1), which protect the cells against apoptosis induced by oxidative stress and hypoxic conditions (Mohammadzadeh et al 2012). Nrf2 is an oxidation/reduction-sensitive transcription factor that plays important role in antioxidant defense (Kensler et al 2007;Lee and Johnson 2004).…”

Mesenchymal Stem/Stromal Cells in Liver Fibrosis: Recent Findings, Old/New Caveats and Future Perspectives

“…Despite the lack of enough in vivo tracking evidence to support any of those views, some articles showed new strategies aiming at prolonging the survival of MSCs in an adverse environment. P2 hBM-MSCs genetically-modified to transiently express cytoprotective factors (i.e., heme oxygenase-1 or nuclear factor erythroid-2 related factor 2), by using adenoviral vectors, were able to survive better in hypoxic and oxidative-stress conditions [86,87].…”