CS Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Syst Biol Reprod Med. 2012 Feb;58(1):33-40. doi: 10.3109/19396368.2011.647381.
This hypothesis and review introduces rules of stem cell stress responses that provide biomarkers and alternative testing that replaces or reduces gestational tests using whole animals. These rules for the stress responses of cultured stem cells validate the organismal strategy of the stress response and show that it emulates what must happen if the conceptus implants during a response to stress in vivo. Specifically there is a profound threshold during a stress dose response where stem cell accumulation is significantly reduced. Below this threshold stress enzymes manage the stress response by converting anabolic to catabolic processes and by suppressing apoptosis, without affecting differentiation. However above this threshold the stem cell survival response converts to an organismal survival response where stress enzymes switch to new substrates and mediate loss of potency factors, gain of early essential differentiated lineages, and suppression of later essential lineages. Stressed stem cells 'compensate' for lower accumulation rates by differentiating a higher fraction of cells, and the organismal survival response further enhances adaptation by prioritizing the differentiation of early essential lineages. Thus compensatory and prioritized differentiation and the sets of markers produced are part of a response of cultured embryos and stem cells that emulate what must happen during implantation of a stressed gestation. Knowledge of these markers and use of stressed stem cell assays in culture should replace or reduce the number of animals needed for developmental toxicity and should produce biomarkers for stressed development in vitro and in vivo.
这一假说和综述介绍了干细胞应激反应的规则，这些规则提供了生物标志物和替代测试，可以替代或减少使用整个动物进行的妊娠测试。这些关于培养干细胞应激反应的规则验证了生物体应激反应的策略，并表明如果胚胎在体内应激反应过程中着床，那么这一策略就必须发生。具体来说，在应激剂量反应中存在一个深刻的阈值，在此阈值下，干细胞的积累显著减少。在这个阈值以下，应激酶通过将合成代谢转化为分解代谢过程并抑制细胞凋亡来管理应激反应，而不影响分化。然而，在这个阈值以上，干细胞存活反应转化为生物体存活反应，其中应激酶切换到新的底物，并介导效力因子的丧失、早期必需分化谱系的获得以及后期必需谱系的抑制。应激干细胞通过分化更多的细胞来“补偿”较低的积累率，而生物体存活反应通过优先分化早期必需的谱系进一步增强适应能力。因此，代偿性和优先性分化以及产生的标志物集是培养胚胎和干细胞反应的一部分，这种反应模拟了在应激妊娠中着床时必须发生的情况。了解这些标志物并在培养中使用应激干细胞检测应该替代或减少用于发育毒性的动物数量，并应在体外和体内产生应激发育的生物标志物。
