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    • In this study ASC transplantation was able to counteract the

    2018-11-12

    In this study, ASC transplantation was able to counteract the appearance of coagulopathy and encephalopathy, which are the two main clinical features of ALF (Lee and Stravitz, 2011). Transplanted animals had levels of transaminases, INR and ammonia comparable to those of healthy control rats and did not displayed brain edema (data not shown). Consistently with clinical findings, we evidenced lobular necrosis and inflammation in vehicle-treated animals, whereas transplanted animals presented only mild injury. With respect to the phenotype of ASCs in the host liver, immunostaining with human monoclonal Elesclomol Supplier suggested that ASCs exert their therapeutic role by maintaining their fibroblast-like phenotype almost at this early time point. Nonetheless, in few sections ASCs presented an epithelial morphology and expressed epithelial markers as CK-18; thus, it is not possible to exclude that in a longer period of observation ASCs can undergo hepatogenic differentiation although, in previous experiments with four weeks of administration of BM-MSCs in CCl4-treated mice, only a small percentage of MSCs underwent hepatocyte-like differentiation (Sato et al., 2005). The presence of mitotic nuclei in liver sections of transplanted animals and the increase of cyclin D1 and PCNA suggest a trophic activity of ASCs which is in agreement with previous data in mice treated with CCl4 and transplanted with ASCs (Banas et al., 2008). Trophic activity and immunomodulation are considered key features of MSCs and lack of immunogenicity of MSCs was demonstrated in chronic models of liver injury (Sato et al., 2005). Regarding the molecular basis underlying the effects of ASC transplantation, we demonstrated that these cells markedly reduce oxidative stress in the liver of animals with acetaminophen overdose. Oxidative stress plays a pivot role in acetaminophen hepatotoxicity (Knight et al., 2002; James et al., 2003; Cover et al., 2005). Here, we show that rats transplanted with ASCs did not display increased levels of isoprostanes, the most sensitive in vivo marker of oxidative stress (Basu, 2008), neither of 8-OHG, a marker of DNA damage, indicating that ASCs protected the rats from acetaminophen-induced oxidative stress. Consistently, ASC transplantation decreased nitrite/nitrates, which are markers of nitrosative stress, to the levels observed in healthy controls. This appears relevant because nitrogen radicals, particular peroxynitrite, exert a role in acetaminophen toxicity especially through DNA fragmentation (Das et al., 2010). Interestingly, ASCs transplantation was able to inhibit JNK activation. JNK signaling regulates the onset of hepatocyte death both in human and murine paracetamol hepatotoxicity (Gunawan et al., 2006; Henderson et al., 2007; Ghosh et al., 2010). JNK inhibition is not protective in CCl4-mediated or anti-Fas antibody mediated hepatic injury (Gunawan et al., 2006) suggesting specificity for the role of JNK in acetaminophen hepatotoxicity. The following are the supplementary data related to this article.
    Authors\' contribution
    Competing interests
    Financial support
    Acknowledgments FS was supported by a Stem Cell Research PhD Program of the University of Catania, Catania, Italy.
    Introduction Embryonic stem cells (ESCs) display a unique characteristic of pluripotency, namely, the maintenance of self-renewal as well as the potential to differentiate into diverse cell types of all three germ layers (Dejosez and Zwaka, 2012). It is well known that ESCs employ a complex transcriptional regulatory network comprising of Oct3/4, Sox2 and Nanog, among several other factors, to regulate the pluripotency (Boyer et al., 2005; Ng and Surani, 2011). Perturbations of expression of these core pluripotency factors lead to loss of pluripotency and subsequent nonspecific differentiation (Ivanova et al., 2006). Nanog may sustain the self-renewal and undifferentiation state through the regulation of Oct3/4 and Sox2 expression, both of which in turn control the expression of downstream genes important for maintenance of pluripotency or inhibition of differentiation (Loh et al., 2006). By employing genome-wide chromatin immunoprecipitation studies, thousands of direct target genes regulated by Oct3/4, Sox2, Klf4, and Nanog were identified (Loh et al., 2006; Chen et al., 2008; Kim et al., 2008; Marson et al., 2008). Interestingly, many of these targets encode for transcription factors such as Esrrb, Zfp281, and Sall4 which are also crucial for the maintenance of pluripotency (Mitsui et al., 2003; Wang et al., 2008; Zhang et al., 2006a, 2008).