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    • There are limitations to in

    2018-11-08

    There are limitations to in vitro studies, the reductionist approach of focusing on a single stem cell type precludes the prolyl hydroxylase inhibitor to gestational hypoxia that has been shown to occur over longer periods of time and precludes TSC interaction with many fetal and maternal cell types (Chakraborty et al., 2012; Rosario et al., 2008; Alam et al., 2007; Ain et al., 2004). However an advantage of the reductionist approach is to understand substantial periods of hypoxic stress that could occur from E2.5–E6.5 before experimental hypoxia was first applied at E6.5 in the rodent gestational model. In addition hypoxia may compound with other stressors or etiologies of hypoxia may change and synergize over time creating longer exposures, despite the adaptation occurring in the models studied to date. A pathophysiologically relevant local level of hypoxic at the implantation site is 0.5% O2, but this cannot be applied systemically to gestational females as it may cause severe systemic effects. The ability to model local hypoxic effects is another advantage of the culture model. Another profound limitation of the studies analyze here is in the use of biochemical assays to assay stress-induced changes in TSC populations which are heterogeneous before and after stress. From the studies performed here it is not possible to conclude whether all cells have a similar decrease in potency and increase in differentiation factors, or whether subpopulations of cells account for all of the potency decrease and differentiation increase. Future studies must use assays that study the stress induced changes in population size and marker intensity and also the fate of stem cells after stress. We have found that stressed, cultured ESCs also undergo prioritized differentiation and these studies were also limited by using solely of biochemical assays (Slater et al., 2014). However in a follow-up study double, viable potency reporter ESCs were made and gave results similar to the biochemical assays (Li et al., 2014). The advantage of the viable reporter ESCs is that they can also be used with flow cytometry and fluorescence activated cell sorting to determine changes in subpopulation size and intensity and also to determine the fate of the cells after potency decrease. Gestational hypoxia has revealed that placental and uterine hormones that are unnecessary during normal development become essential during hypoxic stress in vivo (Xie et al., 2011; Rappolee et al., 2013). In addition, gestational hypoxia produces a phenotype in vivo that has similarities with the phenotype observed here during hypoxia in culture. In both cases there was an increase in pTGC and a suppression of labyrinthine placenta. A key interpretation from the data analyzed here is that stress leads to decreased stem cell growth and the further depletion of stem cell multipotency to enable differentiation of early essential function. A similar outcome is seen in preeclamptic human placenta where proliferative cytotrophoblasts are depleted while differentiated villous surface functions are maintained (Longtine et al., 2012). Stress induces differentiation but hypoxia for stemness, 0.5% O2, truncates this and leads to rapid but incomplete differentiation that suppresses all lineages and two lineages at the labyrinthine surface are suppressed the most. This is probably due to failure to depart from aerobic glycolysis and activate mitochondria (Table 1). The mechanisms mediating the suppression are important to understand since diseases such as intrauterine growth retardation and preeclampsia can feature labyrinthine dysfunction. It is important to test for these hypoxic stress effects in gestational rodent models and in human first trimester villous explants or human TSCs. The following are the supplementary data related to this article.
    Acknowledgments
    Introduction Stem cells play crucial roles in tissue growth, homeostasis and regeneration. The self-renewal capacity of stem cells and their potential to maintain the tissue depend on their ability to regulate endogenous and exogenous (e.g. irradiation) genotoxic stresses. The accumulation of DNA damage and consequent loss of genome integrity due to double strand breaks (DSBs) are two of the major causes of apoptosis, senescence and aging, including in stem cells (Lombard et al., 2005; Nijnik et al., 2007; Rossi et al., 2007; Ruzankina et al., 2008). In the small intestine, stem cells at the bottom of the crypt are proliferating and radioresistant, whereas those around the +4 position are quiescent and radiosensitive (Hua et al., 2012; Li and Clevers, 2010; Potten et al., 2009), therefore the response of stem cells to DNA damage can be distinct depending on their origin, cell cycle status, or both. In another report, melanocyte stem cells did not undergo detectable ionizing radiation (IR)-induced apoptosis, but the stem cell niche was depleted due to their differentiation (Inomata et al., 2009).