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  • br Stem cell based therapies In the previous years excessive

    2020-11-18


    Stem cell–based therapies In the previous years, excessive efforts have been conducted to induce the least aggression and more efficient sources of human cardiomyocytes for different application, particularly for myocardial regeneration. The pluripotent stem cell seems to be an appropriate candidate, due to its proliferate properties and its ability to distinguish into various cell types including cardiomyocytes [7]. Stem Cell based therapy has the probable to activate endogenous regenerative processes, containing the recruitment of resident stem and progenitor CB-5083 synthesis and the motivation of cardiomyocyte proliferation [8]. Secretion of soluble factors is the predominant mechanism of stem cell mediated heart regeneration [9]. Cytokines and growth factors like Transforming Growth Factor (TGF)-β, Stromal Cell-Derived Factor (SDF)-1, and Vascular Endothelial Growth Factor (VEGF), can be secreted by transplanted stem and progenitor cells into the intestinal space or bloodstream that stimulates numerous regenerative processes, for instance, neovascularization, activation of tissue intrinsic progenitor cells, decreased apoptosis of endogenous cardiomyocytes, and enrolment of cells of assistance for tissue repair [9,10]. Some biomarkers, like IL-15, IL-5 and SCF, associate with an improved cardiac function via stem cell treatment representing that higher levels of specific circulating cytokines are appropriate as choice principles for cell-based therapies [11]. The preclinical and clinical trials of stem cell therapy in heart failure and also advantages and disadvantages of these cells for cardiac regeneration are summarized in Table 1, Table 2, Table 3, respectively.
    Conclusion
    Conflict of interest
    Acknowledgments The authors would like to thank the Aging Research Institute, Tabriz University of Medical Sciences, for supporting this work.
    Main Text Embryonic stem cell (ESC) pluripotency is maintained by key transcription factors (TFs) including Oct4, Sox2, and Nanog (collectively referred to as OSN). OSN bind to enhancers and clusters of enhancers called super-enhancers (SEs) driving the expression of pluripotency genes, hence promoting self-renewal (Boyer et al., 2005, Whyte et al., 2013). OSN also bind to the regulatory region of repressed or poorly expressed genes. At these sites, OSN cooperate with Polycomb Repressive Complex 2 (PRC2) (Bernstein et al., 2006, Marson et al., 2008), a factor that promotes the establishment of repressed chromatin states through the trimethylation of histone H3 on lysine 27 (H3K27me3). OSN therefore cooperate with either co-activators or co-repressors such as PRC2 at different regulatory elements, but how this selectivity is achieved remains unresolved (Orkin and Hochedlinger, 2011, Young, 2011). In this issue of Molecular Cell, Wang and colleagues provide one piece of the answer to this conundrum by showing that the histone chaperone and elongation factor Spt6 prevents PRC2 recruitment to key ESC SEs (Wang et al., 2017). Wang et al. then performed chromatin immunoprecipitation-sequencing (ChIP-seq) experiments to identify Spt6 binding sites in ESCs. As expected from its role as a transcription-associated histone chaperone (Ivanovska et al., 2011), they found Spt6 associated with the promoter and the gene body of expressed, but not inactive, genes. Perhaps more unexpectedly, the authors also found Spt6 associated with many enhancers and even more so with SEs. Spt6 occupancy was particularly high at SEs of several key pluripotency genes, including the OSN. These results prompted them to look at the activity of enhancers and SEs in Spt6 knockdown ESCs. Upon Spt6 knockdown, H3K27 acetylation (H3K27ac), a mark associated with enhancer activity (Calo and Wysocka, 2013), decreased preferentially at SEs, including those of key pluripotency TFs. Interestingly, this was accompanied by a decrease in H3K27ac at the associated promoters. Importantly, global H3K27ac levels did not change, suggesting that Spt6 helps maintain H3K27ac specifically at key SEs and their target promoters. Another mark of enhancer activity, the production of non-coding RNAs called eRNAs, was also reduced at these SEs, further supporting the idea that Spt6 promotes the activity of key ESC SEs. A key observation in this study was that H3K27me3, the repressive mark inscribed by PRC2, increased at those same SEs and associated promoters upon Spt6 knockdown, suggesting that the presence of Spt6 at these key SEs may prevent PRC2 recruitment.