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  • Embryonic stem cells ESCs are widely

    2018-10-20

    Embryonic stem muscarinic receptor antagonists (ESCs) are widely used to study early differentiation processes (Posfai et al., 2014). They also hold promise for therapeutic approaches in the field of regenerative medicine (Dressel, 2011; Dressel et al., 2008; Song et al., 2015; Tang and Drukker, 2011). Yet, immune rejection resulting from mismatch histocompatibility is a potential limitation of stem cell-based therapies, restricting the rate of successful transplantation (Zhao et al., 2011; Jin et al., 2015). Moreover, ESC transplantation may hold the risk of teratoma formation because undifferentiated ESCs give rise to teratomas, which resemble benign tumors that consist of tissues derived from the three embryonic germ layers (Przyborski, 2005; Lee et al., 2013). Accordingly, teratoma formation assays need to be performed to confirm ESC pluripotency in a complex in vivo environment. Teratoma assays are also pursued as a model to investigate the crosstalk between ESCs and stromal cells (Przyborski, 2005; Dressel, 2011). We previously generated Evi-overexpressing mouse ESCs (Evi-GOF) via knockin into the ROSA26 locus to study Wnt secretion in ESCs (Augustin et al., 2012). Evi-GOF ESCs showed enhanced Wnt activity, which had no effect on ESC pluripotency and viability. Teratoma experiments with Evi-GOF ESCs confirmed pluripotency characterized by meso-, endo- and ectodermal lineage differentiation although Evi-GOF ESCs revealed a preference for cardiomyocyte differentiation. Based on these findings, the present study was aimed at investigating Evi during teratoma formation in order to clarify the role of Wnt secretion in teratoma–stroma interactions in a definite genetic setting.
    Results
    Discussion ESCs have the potential to differentiate in all types of cells. In vivo application of undifferentiated ESCs leads to teratoma formation (Dressel et al., 2008; Song et al., 2015). A recent screening study identified an involvement of Wnt signaling in the transition from benign to malignant teratocarcinoma growth (Liu et al., 2012). Moreover, upregulated Evi expression was found in human teratomas supporting the hypothesis that Evi may contribute to germ cell tumor progression. The Evi-transgenic ESC line reported in this study provides a novel research tool to study teratoma formation. Evi-GOF teratomas showed enhanced tumor growth demonstrating a tumor-promoting role of Evi in ESCs. Correspondingly, previous experiments in glioblastoma and colorectal tumor cells had shown that loss of Evi resulted in inhibition of tumor growth after xenotransplantation (Augustin et al., 2012; Voloshanenko et al., 2013). Previous studies have focused on the analysis of tumor infiltrating T cells. In turn, much less is known about the role of B cells in modulating the immune response to solid tumors (Nelson et al., 2010). It has been shown for melanoma and several other types of tumors that B cell density correlates with T cell density indicating that B cells support the antitumor immune response (Zirakzadeh et al., 2013). Accordingly, our study also revealed a concomitant reduction of tumor-infiltrating T and B cells.
    Material and methods
    Authorship contribution
    Acknowledgements
    Introduction Clinical and experimental observations made over the years have revealed that pre-transplant myeloablation is associated with an increase in marrow adipogenesis, which has a negative impact on post-transplant hematopoietic repopulation (Snyder, 1965; Naveiras et al., 2009). However, the cause of such post-myelosuppression bone marrow (BM) adipogenesis has been poorly investigated. BMP4 appears to be an essential cytokine secreted in the BM microenvironment, since abrogation of its secretion post-myelosuppression impairs hematopoietic recovery (Goldman et al., 2009). In addition to its important role in hematopoietic regeneration post-transplant, BMP4 is also known to commit embryonic fibroblasts (C3H10T1/2) to the adipocyte lineage (Tang et al., 2004; Bowers et al., 2006; Suenaga et al., 2013), but whether it has a similar adipogenic effect on bone marrow-derived mesenchymal stromal cells (BMSC) is not known. Similarly, whether BMP4 has any role in post-myelosuppression marrow adipogenesis has not been investigated. Given the important role played by BMP4 in post-transplant hematopoietic recovery and its adipogenic capabilities, we hypothesized that there could be an increase in secretion of BMP4 in the BM microenvironment post-myelosuppression to facilitate hematopoietic recovery, which would, however, also cause BMSCs to commit to adipocyte lineage. We propose that this contributes to increased adipocyte formation post-myelosuppression. We report here the findings from our studies carried out to test this hypothesis.