We have demonstrated also in this study that

We have demonstrated also in this study that inhibition of the cellular antioxidant mechanism could promote differentiation of GICs. We also observed that GICs have an enhanced antioxidant mechanism compared to their serum-differentiated counterparts. Based on these findings, we speculate that GICs may need to actively maintain their intracellular ROS levels below a threshold to prevent loss of self-renewal and premature differentiation. Indeed, cancer stem hcv virus have been associated with lower levels of intracellular ROS than non-stem cancer cells in human breast cancers and in head and neck cancers (Diehn et al., 2009). Thus, it would also be interesting to speculate that the ROSlow phenotype is a common property of cancer stem cells required for the maintenance of their self-renewal capacity. However, even if it is actually the case, we need to be reminded that this does not necessarily imply that an increase in the intracellular ROS level is the “physiological cue” for the loss of the stem-like properties and tumor-initiating capacity of GICs. Indeed, our data indicated that inhibition of the ROS–p38 axis alone failed to have a discernible effect on and therefore was not required for normal tumor growth. In contrast, our data at the same time indicated that the activation of the ROS–p38 axis has a significant inhibitory effect on tumor growth. Since the intracellular ROS level is elaborately maintained low through a network of antioxidant enzymes and nuclear factors that control them (Zhang et al., 2010), interventions to perturb either each enzyme or this network system as a whole would therefore be of therapeutic benefit.
Conflict of interest statement
Acknowledgments We thank Drs. Tomoki Todo and Nobuhito Saito at the University of Tokyo for generously providing us with the TGS01 cells and Dr. Tomoko Kagawa for her continuous support/encouragement. This work was supported by Grants-in-Aid for Scientific Research, for Challenging Exploratory Research, and for Young Scientists from the Ministry of Education, Culture, Sports, Science and Technology of Japan, by a Grant-in-Aid from the Global COE Program of the Japan Society for the Promotion of Science, by the National Cancer Center Research and Development Fund (23-A-20), and by a grant from the Japan Brain Foundation.
Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective therapeutic modality for young patients with severe aplastic anemia (SAA) who have an immediate HLA-identical donor. However, less than 30% of patients who require allogeneic HSCT have a human leukocyte antigen (HLA)-compatible sibling. In China, searching for HLA-matched donors is usually unsuccessful because no siblings are available for almost all young people. Fortunately, haplo-identical hematopoietic stem cell transplantation (haplo-HSCT) has come into clinical use to treat hematologic malignancies and the protocols have been greatly improved during the last decade (Guo et al., 2009; Lazarus et al., 2005). However, the results of haplo-HSCT in patients with SAA have been disappointing, due to high risk of treatment-related mortality (TRM) because of infection, bleeding, regimen-related toxicity, engraftment failure, and acute and chronic graft-versus-host disease (aGVHD, cGVHD) (Woodard et al., 2004; Lazarus and Koc, 2001; Tsutsumi et al., 2004; Tabbara et al., 2002). Mesenchymal stem cells (MSCs) are a heterogeneous subset of multipotent stromal stem cells, which express low levels of class I, but not class II, histocompatibility antigens and are not immunogenic in in vitro assays or preclinical models (Le Blanc et al., 2008; D.P. Lu et al., 2006; L.L. Lu et al., 2006). MSCs have also been shown to suppress primary and ongoing mixed lymphocyte reactions (Klyushnenkova et al., 1998; Di Nicola et al., 2002; Ball et al., 2007). MSCs can be isolated from many adult tissues, including bone marrow (BM), periosteum, adipose tissue, fetal liver, cord blood and umbilical cord (UC) tissues (In\'t Anker et al., 2003; Lee et al., 2004; Romanov et al., 2003). Recently, some experimental and clinical data demonstrated that BM-MSCs can support hematopoiesis, enhance the engraftment of HSCs, and reduce the incidence of GVHD following HSCT (Guo et al., 2009; Lazarus et al., 2005). However, the aspiration of BM involves invasive procedures, and the frequency and differentiation potential of BM-MSCs decrease significantly with age (D.P. Lu et al., 2006; L.L. Lu et al., 2006). Lu LL et al. have shown that a large number of MSCs can be easily isolated from the UC and collected using an accessible and painless procedure (D.P. Lu et al., 2006; L.L. Lu et al., 2006). Our recent data demonstrated that the modified haplo-HSCT combined with third-party donor-derived UC-MSCs for 50 patients with refractory/relapsed hematologic malignancy was not only safe and feasible but also effective for the improvement of donor engraftment and the reducing of severe GVHD (Wu et al., 2013). However, it is still unknown whether cotransplantation of UC-MSCs in haplo-HSCT recipients with SAA can reduce graft failure.