CSF-1 Signalling Sustains Trophoblast Function via Dkk-1 in Fetal Growth Restriction.

Abstract

Fetal growth restriction (FGR) is a major pregnancy complication associated with stillbirth and lifelong cardiometabolic risk, most commonly arising from placental insufficiency characterised by defective trophoblast function. Colony-stimulating factor-1 (CSF-1) and its receptor, CSF-1 receptor (CSF-1R), are critical regulators of trophoblast proliferation, differentiation and invasion, yet their role in FGR pathogenesis remains poorly understood. Here, we demonstrate that CSF-1 and CSF-1R expression are significantly reduced in FGR placentae across both first trimester chorionic villus samples (CVS) and third trimester tissues compared to gestational age-matched controls. Using cultured villous cytotrophoblast (VCT), choriocarcinoma derived-BeWo cells and placental explant models, we show that CSF-1R signalling regulates trophoblast differentiation and human chorionic gonadotrophin (beta-hCG) production, and that CSF-1R inactivation upregulates specificity protein 1 (SP1) and suppresses MYB proto-oncogene (MYB), transcription factors with concordant dysregulation in FGR and small-for-gestational-age (SGA) placentae. Using human trophoblast-derived placental organoids exposed to hypoxic, inflammatory and oxidative stress conditions, together with a 105-cytokine proteome profiler assay, we identified dickkopf-1 (Dkk-1) as a lead candidate secretory protein that was consistently reduced across all three FGR-like insults. CSF-1 co-treatment restored Dkk-1 secretion and increased Dkk-1 expression intensity in cytotrophoblasts under hypoxic and inflammatory conditions. These findings identify CSF-1/CSF-1R signalling as a dysregulated axis in FGR pathogenesis, with Dkk-1 secretion identified in vitro as a candidate downstream mediator and establish CSF-1 supplementation as a candidate therapeutic strategy for placental dysfunction.Copyright © 2026, The Authors. All rights reserved.