The field of stem cell therapeutics is moving ever closer to widespread application in the clinic. However, despite the undoubted potential held by these therapies, the balance between risk and benefit remains difficult to predict. As in any new field, a lack of previous application in man and gaps in the underlying science mean that regulators and investigators continue to look for a balance between minimizing potential risk and ensuring therapies are not needlessly kept from patients. Here, we attempt to identify the important safety issues, assessing the current advances in scientific knowledge and how they may translate to clinical therapeutic strategies in the identification and management of these risks. We also investigate the tools and techniques currently available to researchers during preclinical and clinical development of stem cell products, their utility and limitations, and how these tools may be strategically used in the development of these therapies. We conclude that ensuring safety through cutting-edge science and robust assays, coupled with regular and open discussions between regulators and academic/industrial investigators, is likely to prove the most fruitful route to ensuring the safest possible development of new products.

Background: Nrf2 has been implicated in regulating immune cell signaling and function.Results: Nrf2-deficient murine DCs exhibit enhanced maturation phenotype, increased ROS levels with dysregulation of antigen uptake capabilities, and altered intracellular signaling.Conclusion: Nrf2 regulates DC intracellular redox and immune function.Significance: Defining the role of Nrf2 in DC biology underpins development of potential Nrf2 targeted immunotherapeutics.

Background: HO-1 contributes to redox homeostasis and regulation of immature dendritic cell (DC) phenotype.Results: HO-1 inhibition results in increased ROS, activation of p38 MAPK-CREB/ATF1 pathway, and dysregulation of DC phenotype and function.Conclusion: HO-1 influences DC function through effects on p38 MAPK-CREB/ATF1 signaling pathway.Significance: This study provides new insights into the molecular pathways influenced by HO-1 in DCs.

Background: Nrf2 is required for normal dendritic cell immune functions.Results: Loss of Nrf2 alters DC function and results in hyperphosphorylation of CREB/ATF1 transcription factors that are responsive to p38 MAPK inhibition.Conclusion: The p38 MAPK-CREB/ATF1 axis contributes to Nrf2-mediated regulation of DC function.Significance: Defining the relevance of p38-CREB/ATF1 in Nrf2 signaling expands understanding of DC biology.