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    • Many studies Lee et al Fischer et

    2018-11-08

    Many studies (Lee et al., 2009; Fischer et al., 2009) have reported that intravenously injected BMSCs are initially trapped in the lung. However, it has also been shown that pulmonary trapping of infused apexbio dilution may be a transient phenomenon. Intravenously injected BMSCs or peripheral blood stem cells (PBSCs) accumulate initially in the lung when observed in an hour after injection (Gao et al., 2001; Daldrup-Link et al., 2004; Schrepfer et al., 2007), and redistribute to liver, spleen, kidney and BM 48h later (Gao et al., 2001; Daldrup-Link et al., 2004). Rochefort et al. found a 50–60% pulmonary accumulation of BMSCs 1h after infusion and this percentage went down to about 30% 3h post injection (Rochefort et al., 2005). Kang et al. reported that intravenous injection of PBSCs had a high lung uptake at 30min, and the initial lung uptake was cleared 2h later after injection. At 4h after the injection, the distributions of the intravenously injected PBSCs were 42.12% in spleen, 21.3% in liver and only 5.8% in lung (Kang et al., 2006). In our experimental model, while many of the injected BMSCs were in the lung, a substantial fraction of cells could be found in the spleens and other organs of the recipient mice 2days after the injection. Several reasons apexbio dilution might be involved in this phenomenon. First, cell size has been considered as a key factor in the pulmonary trapping BMSCs. A single dose of 950cGy irradiation might injure the pulmonary capillary endothelium and increase the pulmonary capillary filtration coefficient (Suzuki et al., 1999), which may improve the passage of BMSCs. Second, BMSC infusion with two injections had been used in our experiments, which might result in an increased pulmonary passage as compared to a single injection. Third, BMSCs in the lethal aGvHD mice 2days after the injection were likely to further located into spleen by splenic inflammation induced by aGvHD, like the intravenously injected neural stem cells (NSCs) reaching the lymph nodes of mice with intracerebral hemorrhage (ICH) or experimental autoimmune encephalomyelitis (EAE) (Lee et al., 2008; Einstein et al., 2007). Our results have also shown that the production of IL-6 and PGE2 is pivotal in Notch-mediated immuno-suppression effects of BMSCs on DCs. PGE2 inhibits T-cell activation and proliferation, and is synthesized by phospholipase A2 and COX from arachidonic acid released from cellular membrane phospholipids (Fitzpatrick and Soberman, 2001). Two isoforms of COX have been found in many types of cells. COX-1 is expressed constitutively in most mammalian tissues and is responsible for housekeeping functions of PGs such as the regulation of gastric acid secretion. COX-2, in contrast, is an inducible form and is induced by a variety of cytokines during proinflammatory responses. A complex of NIC and RBP-J has been shown to bind to COX-2 promoter and elevate COX-2 expression in SC-M1 cells (Yeh et al., 2009). This finding was consistent with our results showing that the production of PGE2 was reduced significantly in BMSCs when RPB-J gene was knocked out. IL-6 plays a major role in the regulation of immune response, hematopoiesis, inflammation and oncogenesis (Kishimoto, 2010). A variety of transcription factors including AP1, C/EBP and nuclear factor (NF)-κB are involved in the regulation of IL-6 expression (Plaisance et al., 1997). The NF-κB family of proteins is the key regulator of IL-6 gene transcription, and conserved binding motifs for NF-κB were identified between −73 and −64bp upstream to the transcriptional start site of the IL-6 promoter (Libermann and Baltimore, 1990). A RBP-J protein-binding motif has been identified within the NF-κB-binding sites, and RBP-J can bind to this region (Plaisance et al., 1997; Palmieri et al., 1999). RBP-J has been shown as a constitutive silencer of the IL-6 gene in the absence of NF-κB, and functions as a modulator of NF-κB binding and transactivation, presumably by limiting the access of NF-κB to DNA (Plaisance et al., 1997; Palmieri et al., 1999). However, RBP-J-deficient murine macrophages produced less IL-6 upon LPS stimulation (Wongchana and Palaga, 2012; Wang et al., 2010b). Overexpression of NIC in RAW264.7 macrophages resulted in significantly higher IL-6 expression than the control, which could be completely abrogated by a NF-κB inhibitor (Wongchana and Palaga, 2012). Consistently, in the current study, IL-6 expression in BMSCs decreased significantly upon RBP-J gene knockout (Osipo et al., 2008).