Characterization of senescence-associated transcripts in the human placenta.

Introduction: Fusion of mononucleated cytotrophoblasts into syncytium leads to trophoblast senescence. Yet, premature senescence is associated with preeclampsia, fetal growth restriction (FGR), and related obstetrical syndromes. A set of 28 transcripts that comprise senescence-associated secretory phenotype (SASP) was recently described in placentas from women with preeclampsia. We posited that this transcript set is uniquely regulated in late-term placentas or in placentas derived from participants with major obstetrical syndromes.

Methods: Using our large placental RNAseq bank, we analyzed data from healthy participants (n = 33) with histologically normal placentas, representing delivery at 37-41 weeks. To represent diseases, we included RNAseq data from participants (n = 220) with severe preeclampsia, FGR, FGR with a hypertensive disorder (FGR + HDP), or spontaneous preterm delivery, and healthy controls (n = 129). We also assessed the expression of several SASPs in primary human trophoblasts that were exposed in vitro to hypoxia, reduced differentiation, or ferroptotic or apoptotic signals.

Results: Among the 28 SASP transcripts analyzed, eight had a significant change between deliveries at <37 weeks vs ≥ 41 weeks, including upregulation of FSTL3, IL1RL1, INHBA, and VEGFA and downregulation of STC1, RARRES2, MRC2, and SELP. The expression of SASP mRNAs was enriched in the placentas from the assessed syndromes, with most expression changes in placentas from FGR/HDP. Our in vitro analysis associated hypoxia or apoptosis with altered expression of FSTL3, VEGFA, and DKK1.

Discussion: A set of placental SASPs defines late-term placentas, placental dysfunction-related clinical syndromes, and in vitro-defined trophoblast injury. Trophoblastic SASP signatures may assist in characterizing placental senescence in health and disease.