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  • GW311616 hydrochloride It seems plausible that this ESC driv


    It seems plausible that this ESC-driven effect relies on a paracrine signaling. Numerous studies showed that the Fgf4 (fibroblast growth factor 4)/MAPK (mitogen-activated protein kinase) pathway is involved in PE differentiation in mouse GW311616 hydrochloride (Chazaud et al., 2006), GW311616 hydrochloride (Frankenberg et al., 2011), (Grabarek et al., 2012), (Kang et al., 2013), (Krawchuk et al., 2013), (Nichols et al., 2009) and (Yamanaka et al., 2010). It is known that in the blastocyst the synthesis of Fgf4 occurs predominantly in the EPI precursor cells, while Fgf receptor – Fgfr2 is specific for PE and TE lineages (Guo et al., 2010) and (Kurimoto et al., 2006). However, it is unlikely that Fgf4 alone is responsible for the observed change of the pattern of differentiative vs. conservative divisions earlier in development, i.e. during 8- to 16-cell stage transition. In order to verify this possibility, we cultured 8-cell stage embryos (without introduced ESCs) in the presence of exogenous Fgf4 till the 16-cell stage and observed no effect on the frequency of conservative divisions during this transition (data not shown). Nevertheless, we cannot exclude the involvement of Fgf/MAPK in the phenomenon observed at the blastocyst stage, i.e. the lack of EPI chimerism. We have previously proved that a bias in the expression of Fgf4 and Fgfr2 exists as early as at the 32-cell stage, i.e. cells originating from the second wave of differentiative divisions express Fgfr2 more frequently than the daughter cells of primary inner blastomeres, which have higher and more frequent expression of Fgf4 (Krupa et al., 2014). In our published model (Krupa et al., 2014) we postulated the existence of Fgf4-dose-dependent dialog, in which Fgf4-positive blastomeres instruct the Fgfr2-positive cells to acquire PE fate. Moreover, Yamanaka et al. (2010) showed that blastocysts originating from the 8-cell stage embryos cultured in high doses of exogenous Fgf4, contains ICM built exclusively of PE cells. These experiments proved that all ICM cells, including EPI precursors (despite lower expression of Fgfr2), have the potential to respond to Fgf4 induction and, in consequence, to specify toward PE. This is only possible in high concentration of Fgf4 (not observed in physiological conditions in the embryo), which imposes a change in the direction of EPI progenitors differentiation. In line with this, it seems plausible that the production and secretion of Fgf4 by the ESCs (Schoorlemmer and Kruijer, 1991) and (Wilder et al., 1997) in a dose-dependent manner (i.e. the more ESCs introduced, the higher level of secreted Fgf4) is responsible for differentiation of the inner blastomeres toward the PE (the higher level of Fgf4, the more host embryo inner cells contribute to PE). Taken together, in this study we explored an interesting experimental model, which addresses the effect of supernumerary inner-like cells on the pattern of blastomere divisions and specification of the first embryonic cell lineages. We showed that the presence of supernumerary inner cells (i.e. ESCs) and their slightly altered geometry enforce conservative divisions of blastomeres, eventually leading to a decrease in embryo-derived inner cells. Moreover, we postulate that the presence of ESCs affects the specification of host embryo cells within the ICM. The mechanism responsible for the bias in differentiation of the inner embryonic cells toward EPI fate remains elusive. Additional studies are needed to evaluate the involvement of a paracrine FGF-dependent signaling in the observed phenomenon.
    Materials and methods
    Grant funding This work was supported by the grant OPUS 2013/09/B/NZ3/02404 from the National Science Center (Poland).
    Introduction The well-known damage mechanisms environmental stress cracking (ESC) and slow crack growth (SCG) are relevant for a broad range of applications, especially for high-density polyethylene (PE-HD) [[1], [2], [3], [4]]. PE-HD is used in a large variety of high-performance applications, e.g. in packaging as material for jerrycans, drums and intermediate bulk containers (IBC) [5] for storage and transport of various liquid media. SCG and ESC have to be considered the major causes of failure in these applications [6] and, therefore, test procedures addressing these phenomena and the resistance of PE materials against them are essential.