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    • br Conclusions In summary our

    2018-11-06


    Conclusions In summary, our current study identified Zfp819 as a novel-pluripotency related gene and shows its function in regulation of ERV expression in pluripotent stem cells. In support of these findings, we identified the interaction of Zfp819 with KAP1, a universal co-repressor of KRAB proteins, which function in suppression of ERVs. Our findings thus highlight that Zfp819 functions in genomic integrity maintenance mechanisms of ESCs through its interaction with KAP1 and Chd4.
    Acknowledgments The authors would like to thank Ms. Sandra Meyer for microarray data analysis and Ms. Marieke Wolf for helping with DNA methylation studies. This work was partly supported by the German Research Foundation (Deutsche Forschungsgemeinschaft)DFG SPP1356 (EN 84/22-1; ZE 442/4-1 and 4-2) and DFG FOR 1041 (EN 84/23-1; ZE 442/5-1 and 5-2).
    Introduction Bone marrow stromal hippo signaling pathway (BMSCs) which are also known as mesenchymal stromal cells (MSCs) were first described by Friedenstein et al. (1966). They have anti-inflammatory and immunosuppressive properties and are being tested in a large number of clinical trials for many different applications (Ciccocioppo et al., 2011; Dash et al., 2009; Hare et al., 2009; Joyce et al., 2010; Karussis et al., 2010; Le Blanc et al., 2004; Mazzini et al., 2010; Pal et al., 2009; Saleem et al., 2000). In most cases a relatively small number of BMSCs are isolated from bone marrow aspirates or bone biopsies by plastic adherence and expanded by serial passage. The typical cell dose is 1 to 2×106cellsperkg of recipient weight or 75 to 200×106 cells. The production of those doses of BMSCs from 10 to 15mL of aspirated marrow requires the expansion of BMSCs over 3 to 4weeks. The expansion capability of BMSCs, however, is limited. Prolonged BMSC culture leads to deterioration of their replication ability and eventually to senescence (Ksiazek, 2009; Wagner et al., 2010). Those changes are associated with morphological changes, a reduction in proliferation ability, the loss of the ability to differentiate into bone, cartilage and adipose tissue (Banfi et al., 2000; Digirolamo et al., 1999; Sethe et al., 2006; Tanabe et al., 2008) and the down-regulation of stemness-related and DNA repair genes (Galderisi et al., 2009). Indiscriminate use of senescent BMSCs in clinical trials may lead to negative results and compromise the entire nascent field of BMSC therapy.
    Material and methods
    Results
    Discussion While BMSCs are being used clinically to treat a wide variety of conditions, the results of these clinical trials have been variable. This may be due in part to differences in BMSC manufacturing methods. One variable among BMSC manufacturing methods is the number of passages used to produce the final product. Some laboratories use 3 or 4 passages while others use 5 or 6 passages (Horwitz et al., 2002; Koc et al., 2000, 2002; Le Blanc and Ringden, 2007; Le Blanc et al., 2003). It is known that prolonged culture of BMSCs is associated with the loss of proliferation potential and likely the loss of function (Banfi et al., 2000; Tanabe et al., 2008). We characterized changes that occurred in BMSCs with prolonged culture and found that molecular changes preceded phenotype and functional changes. The marked differences in molecular signatures between early and late passages occurred over multiple passages and the timing of these changes varied among individuals. When the molecular signatures of each donor\'s BMSC samples were analyzed individually, we noticed that the BMSC samples were clustered from lowest to highest passages for all 7 donors. This is consistent with the results of Schallmoser et al., (2010) and Wagner et al. (2008), who analyzed serial passages of BMSCs from three donors. These results suggest that some changes in BMSCs occur with each passage; however, the magnitudes of these changes with each passage are minor relative to the difference between the earliest and latest passage cells. This also provides further evidence that the transition from an early to late passage phenotype is gradual and all early passage cells may not have identical functional properties.