Molecular pathways of senescence regulate placental structure and function

Hilah Gal, Marina Lysenko, Sima Stroganov, Ezra Vadai, Sameh A. Youssef, Keren Tzadikevitch-Geffen, Ron Rotkopf, Tal Biron-Shental, Alain de Bruin, Michal Neeman, Valery Krizhanovsky

Research output: Contribution to journalArticlepeer-review

Abstract

The placenta is an autonomous organ that maintains fetal growth and development. Its multinucleated syncytiotrophoblast layer, providing fetal nourishment during gestation, exhibits characteristics of cellular senescence. We show that in human placentas from pregnancies with intrauterine growth restriction, these characteristics are decreased. To elucidate the functions of pathways regulating senescence in syncytiotrophoblast, we used dynamic contrast-enhanced MRI in mice with attenuated senescence programs. This approach revealed an altered dynamics in placentas of p53−/−, Cdkn2a−/−, and Cdkn2a−/−;p53−/− mice, accompanied by histopathological changes in placental labyrinths. Human primary syncytiotrophoblast upregulated senescence markers and molecular pathways associated with cell-cycle inhibition and senescence-associated secretory phenotype. The pathways and components of the secretory phenotype were compromised in mouse placentas with attenuated senescence and in human placentas from pregnancies with intrauterine growth restriction. We propose that molecular mediators of senescence regulate placental structure and function, through both cell-autonomous and non-autonomous mechanisms.

Original languageEnglish
Article numbere100849
JournalEMBO Journal
Volume38
Issue number18
DOIs
StatePublished - 16 Sep 2019
Externally publishedYes

Keywords

  • gelatinase
  • intrauterine growth restriction
  • placenta
  • senescence
  • syncytiotrophoblast

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