Hypoxic stress induces, but cannot sustain trophoblast stem cell differentiation to labyrinthine placenta due to mitochondrial insufficiency

摘要: Dysfunctional stem cell differentiation into placental lineages is associated with gestational diseases. Of the differentiated available to trophoblast cells (TSC), elevated O2 and mitochondrial function are necessary at maternal-placental surface important in etiology of preeclampsia. TSC lineage imbalance leads embryonic failure during uterine implantation. Stress implantation exacerbates depletion by decreasing proliferation increasing differentiation. In an site normally ~2%. culture, exposure 2% fibroblast growth factor 4 (FGF4) enabled highest mouse multipotency proliferation. contrast, hypoxic stress (0.5% O2) initiated most after 24h despite FGF4. However, supported poorly 4-7 days, FGF4 removal. At all tested levels, maintained Warburg metabolism; inactivity aerobic glycolysis. suppressed membrane potential low cytochrome c oxidase (oxidative phosphorylation/OxPhos), high pyruvate kinase M2 (glycolysis) Inhibiting OxPhos inhibited optimum 20% O2. Moreover, adding differentiation-inducing hyperosmolar failed induce hypoxia. Thus, depended on O2; stresses did not 0.5% Hypoxia-limited inhibition activation suggest that two labyrinthine placenta requires O2>0.5-2% function. Stress-activated protein increases early suppresses later proportion deviation from optimal for multipotency, thus it first enzyme reported prioritize