What does this research mean for the field?

Physiologic hyperglycemia alters trophoblast metabolic and transcriptional profiles but does not impair differentiation, indicating that elevated glucose alone is insufficient to cause the placental dysfunction associated with perinatal diabetes. Novelty: ClaimNovelty.CONTRADICTORY. Consensus alignment: ConsensusAlignment.CHALLENGES_CONSENSUS.

What question did this study set out to answer?

Evaluate the effects of hyperglycemia on trophoblast stem cell metabolism and differentiation under physiologic conditions.

June 7, 2026

2134-P: Hyperglycemia Reprograms Trophoblast Stem Cell Metabolic and Transcriptional Profiles without Impairing Differentiation

Key Points

Evaluate the effects of hyperglycemia on trophoblast stem cell metabolism and differentiation under physiologic conditions.
Cultured human trophoblast stem cells under self-renewing and syncytiotrophoblast differentiation conditions with varying glucose levels for 3 days.
Measured glucose consumption and lactate production, along with histone acetylation and RNA sequencing for gene expression analysis.
Differentiation assessed using immunofluorescence microscopy in 2D and 3D models.
Syncytiotrophoblast (ST) cells showed increased glucose consumption and lactate production by 41% and 50% at 10 mM and 25 mM glucose compared to 5 mM (p<0.001).
Histone acetylation in ST cells increased by >50% in higher glucose concentrations with no changes in self-renewing (SR) cells.
Identified 107 differentially expressed genes in ST cells cultured in 25 mM glucose compared to 5 mM, linked to glucose metabolism and cellular stress.

Abstract

Introduction and Objective: Perinatal diabetes, characterized by maternal hyperglycemia, is associated with abnormal placental development and adverse pregnancy outcomes. Prior studies suggest hyperglycemia disrupts trophoblast metabolism and differentiation but rely on cancer-derived models and non-physiologic media. We evaluated the effects of hyperglycemia on trophoblast stem cell (TSC) metabolism and differentiation under physiologic conditions. Methods: Human TSCs (CT-29, CT-30) were cultured under self-renewing (SR) or syncytiotrophoblast (ST) differentiation conditions in human plasma-like media containing 5, 10, or 25 mM glucose for 3 days. Glucose and lactate were quantified from media, and cells harvested for histone acetylation quantification and RNA-sequencing. Immunofluorescence microscopy assessed differentiation in 2D culture and 3D organoid models. Groups were compared using ANOVA. Results: ST cells consumed more glucose and produced more lactate than SR cells across all glucose conditions, with 41% and 50% higher lactate in 10 and 25 mM glucose, respectively, compared with 5 mM (p0.001). Consistent with known hyperglycemia-epigenetic associations, histone acetylation increased by 50% in ST cells cultured in 10 and 25 mM glucose compared with 5 mM, with no effect observed in SR cells. RNAseq showed no glucose-dependent differential expression in SR cells or between 5 and 10 mM glucose in ST cells, but identified 107 differentially expressed genes (2 log2 fold change, padj0.01) in ST cells cultured in 25 versus 5 mM glucose, enriched for glucose metabolism and cellular stress pathways. No differences in 2D morphology or organoid size or structure were observed. Conclusion: Physiologic hyperglycemia alters trophoblast metabolic and transcriptional profiles without impairing differentiation. These findings suggest that glucose alone is insufficient to disrupt trophoblast differentiation and that additional factors likely contribute to placental dysfunction in perinatal diabetes. Disclosure C. Norbeck: None. S. Jena: None. L. Sadu Murari: None. M.K. Tranowski: None. M. Gearhart: None. E. Alejandro: None. S. Wernimont: None.

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