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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.

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No abstract

Despite many advantages of mesenchymal stem cells (MSCs) that make them suitable for cell therapy purposes, their therapeutic application has been limited due to their susceptibility to several stresses (e.g., nutrient-poor environment, oxidative stress, and hypoxic and masses of cytotoxic factors) to which they are exposed during their preparation and following transplantation. Hence, reinforcing MSCs against these stresses is a challenge for both basic and clinician scientists. Recently, much attention has been directed toward equipping MSCs with cytoprotective factors to strengthen them against unfavorable microenvironments. Here, we engineered MSCs with lipocalin 2 (Lcn2), a cytoprotective factor that is naturally induced following exposure of cells to stresses imposed by the microenvironment. Lcn2 overexpression not only did not interfere with the multidifferentiation capacity of the MSCs but also granted many protective properties to them. Lcn2 potentiated MSCs to withstand oxidative, hypoxia, and serum deprivation (SD) conditions via antagonizing their induced cytotoxicity and apoptosis. Adhesion rate of MSCs to coated culture plates was also enhanced by Lcn2 overexpression. In addition, Lcn2 induced antioxidants and upregulated some growth factors in MSCs. Our findings suggested a new strategy for prevention of graft cell death in MSC-based cell therapy.