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    • Because SAPK mediates hyperosmolar stress induced Hand

    2018-11-08

    Because SAPK mediates hyperosmolar stress-induced Hand1 and Hand1-dependent PL1 (Awonuga et al., 2011), we tested whether stress-induced lineage choice during hypoxia was SAPK-dependent. Since hyperosmolar stress induces the first lineage but not later lineages from TSC (Liu et al., 2009), and SAPK mediates the induction of first lineage markers (Awonuga et al., 2011), we hypothesize that SAPK will mediate induction of the first lineage/marker (pTGC/Hand1) and suppression of later lineage/marker (synTA/Gcm1) induced by hypoxic stress. Here we test for the effects on multipotency and lineage differentiation in cultured TSC of FGF4 removal during TSC culture with O2 levels at 20, 2, 0.5, and 0%. We found that FGF4 maintains Warburg metabolism (suppression of mitochondrial KRCA 0008 transport chain and activation of aerobic glycolysis) at all O2 levels. During hypoxic stress at 0.5% O2 with FGF4 removed, TSC differentiation was induced at days 1–2 that were insufficient to support increased mitochondrial activity or suppress aerobic glycolysis at days 4–7. This led to a rapid but incomplete differentiation and lineage imbalance as two lineages at the maternal interface of the later-developing chorionic placenta are largely suppressed at all O2 levels<20%. Imbalanced TSC differentiation early in pregnancy is one predicted etiology of preeclampsia in humans (Huppertz, 2008; Redman & Sargent, 2005; Redman, 1991; Roberts & Hubel, 2009). An understanding of how hypoxic stress causes lineage imbalance early during mTSC differentiation in a mouse model should produce an understanding of the types of adaptive responses that can also lead to maladaptive pathologies. Mouse models associated with spontaneous miscarriage (Xu et al., 2013; Johnson et al., 2010), preeclampsia (Ahmed et al., 2010; Kumasawa et al., 2011), intrauterine growth retardation (Vogt et al., 1996), and preterm labor have been produced and 80% of genes causing placental phenotypes in mouse are expressed in human placentation (Cox et al., 2009). Thus the understanding of response of mTSCs induced by hypoxia, <2% O2, should provide an insight into the early placental pathology in humans.
    Materials and methods
    Results
    Discussion Since the seminal work from the Fisher lab, O2 effects during imbalanced or blocked placental stem cell differentiation have focused on the insufficient “hypoxia” at 2% O2 (Genbacev et al., 1997) which does not support differentiation. We corroborate and extend those findings here; 2% O2 provides for insufficient placental differentiation for almost all lineages. Specifically 2% O2 is insufficient for the full development of two lineages at the surface of the labyrinthine placenta; gas exchange-mediating synTA cells and secretory sTGCs. In the first trimester in humans it is likely that 2% O2 is normoxic for the villous surface and this sustains differentiation for type 1 markers described here, but type 2 markers require O2>2%. Moreover, in the lacunar stage of all mammals with invasive trophoblasts that support later hemochorial placentation development of complete differentiated function, as represented by type 2 markers, will be truncated. But hypoxia <2% O2 also does not support a continuing increase in PL1 from days 4 to 7 after an early disproportionate increase in PL1 induced by hypoxic stress at day 1. The early increase in Hand1 and decrease in Gcm1 are SAPK-dependent and this enzyme supports Hand1-dependent endoreduplication to produce giant cells and production of PL1 while suppressing the development of the later-arising lineages of the chorion that are Gcm1-dependent (Table 1). Suppression of Gcm1 and syncytiotrophoblast formation is associated with preeclampsia (Chiang et al., 2009; Baczyk et al., 2009; Tache et al., 2013; Drewlo et al., 2008; Soleymanlou et al., 2007). The support of syncytiotrophoblast formation at 20% but not 1% O2 has been reported in first and third trimester cytotrophoblasts, but alternate lineage choice or intracellular enzymatic regulation of the process was not studied (Wich et al., 2009; Robins et al., 2007). It has been reported that increased glycogen synthase kinase 3 (GSK3) increase and decreased phosphoinositol 3 kinase (PI3K–Akt) activities are causal for hypoxia-induced Gcm1 protein degradation also at 1% O2 which also occurs in hypoxia associated preeclampsia (Chiang et al., 2009). Taken together these data, the data here suggest that mechanisms mediated by SAPK early and mitochondrial insufficiency later will play a role in human placental differentiation and disease during responses to hypoxia.