Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses

Placental development is profoundly influenced by oxygen (O-2) tension. Hum an cytotrophoblasts proliferate in vitro under low O-2 conditions but diffe rentiate at higher O-2 levels, mimicking the developmental transition they undergo as they invade the placental bed to establish the maternal-fetal ci rculation in vivo. Hypoxia-inducible factor-1 (HIF-1), consisting of HIF-1 alpha and ARNT subunits, activates many genes involved in the cellular and organismal response to O-2 deprivation. Analysis of Arnt(-/-) placentas rev eals an aberrant cellular architecture due to altered cell fate determinati on of Arnt(-/-) trophoblasts. Specifically, Arnt(-/-) placentas show greatl y reduced labyrinthine and spongiotrophoblast layers, and increased numbers of giant cells. We further show that hypoxia promotes the in vitro differe ntiation of trophoblast stem cells into spongiotrophoblasts as opposed to g iant cells. Our results clearly establish that O-2 levels regulate cell fat e determination in vivo and that HIF is essential for mammalian placentatio n. The unique placental phenotype of Arnt(-/-) animals also provides an imp ortant tool for studying the disease of preeclampsia. Interestingly, aggreg ation of Arnt(-/-) embryonic stem (ES) cells with tetraploid wild-type embr yos rescues their placental defects; however, these embryos still die from yolk sac vascular and cardiac defects.