Hypoxic Stress Forces Adaptive and Maladaptive Placental Stress Responses in Early Pregnancy

This review focuses on hypoxic stress and its effects on the placental lineage and the earliest differentiation events in mouse and human placental trophoblast stem cells (TSCs). Although the placenta is a decidual organ at the end of pregnancy, its earliest rapid growth and function at the start of pregnancy precedes and supports growth and function of the embryo. Earliest function requires that TSCs differentiate, however, "hypoxia" supports rapid growth, but not differentiation of TSCs. Most of the literature on earliest placental "hypoxia" studies used 2% oxygen which is normoxic for TSCs. Hypoxic stress happens when oxygen level drops below 2%. It decreases anabolism, proliferation, potency/stemness and increases differentiation, despite culture conditions that would sustain proliferation and potency. Thus, to study the pathogenesis due to TSC dysfunction, it is important to study hypoxic stress below 2%. Many studies have been performed using 0.5 to 1% oxygen in cultured mouse TSCs. From all these studies, a small number has examined human trophoblast lines and primary first trimester placental hypoxic stress responses in culture. Some other stress stimuli, aside from hypoxic stress, are used to elucidate common and unique aspects of hypoxic stress. The key outcomes produced by hypoxic stress are mitochondrial, anabolic, and proliferation arrest, and this is coupled with stemness loss and differentiation. Hypoxic stress can lead to depletion of stem cells and miscarriage, or can lead to later dysfunctions in placentation and fetal development. Birth Defects Research 109:1330-1344, 2017. © 2017 Wiley Periodicals, Inc.