Trophoblast differentiation and placental aging

Placental aging is the programmed process of progressive functional decline and tissue maturation that occurs throughout the course of pregnancy, particularly in the later stages. While this is a normal feature of development, accelerated or pathological placental aging triggered by stress can impair placental function and lead to serious complications, including stillbirth, preeclampsia, fetal growth restriction, and preterm birth. Understanding mechanisms driving premature placental aging is critical for developing strategies to improve pregnancy outcomes. This proposal tests the hypothesis that precocious trophoblast differentiation leads to exhaustion of the trophoblast stem cell (TSC) pool, triggering premature placental aging and disease. TSCs maintain placental homeostasis by regenerating the syncytiotrophoblast – the multinucleated epithelial layer that mediates nutrient and gas exchange at the maternal-fetal interface. Loss of TSC self-renewal or differentiation under stress may compromise placental regenerative capacity and contribute to aging and failure. Our preliminary data identify the transcription factor CEBPB as a key regulator of the stress response and TSC differentiation. Conversely, trophoblast-associated microRNAs, including the murine miR-290~295 cluster and its human ortholog miR- 371~373, help preserve TSC identity by supporting stem cell self-renewal and metabolism. Loss of miR-290 in mice leads to premature depletion of the TSC pool, the accumulation of aging markers in the placenta, and stillbirth – linking early stem cell dysfunction with placental failure. The overall goal of this project is to define the molecular and metabolic pathways that govern TSC differentiation and placental aging. Aim 1 will characterize stress-induced TSC differentiation and senescence, focusing on the regulatory roles of CEBPB and miR- 371~373. Aim 2 will determine how TSC depletion contributes to placental aging and stillbirth in miR-290 knockout mice, using transcriptomic and histologic approaches. Aim 3 will investigate the role of metabolic reprogramming in TSC fate and aging, and test whether metabolic interventions can preserve stemness under stress. By linking TSC biology with placental aging and adverse outcomes, this work provides a conceptual framework that opens avenues for therapeutic innovation. Applying principles from aging biology to the placenta may enable repurposing of existing anti-aging strategies to reduce placental dysfunction and prevent the most devastating consequence—stillbirth. This project directly addresses the goals of NOSI NOT-HD-23-021: The Road to Prevention of Stillbirth. Project Number: 1R01HD121946-01 | Fiscal Year: 2026 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Jacqueline Parchem | Institution: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON, HOUSTON, TX | Award Amount: $688,009 | Activity Code: R01 | Study Section: Pregnancy and Neonatology Study Section[PN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11359700