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Abstract

Maternal obesity, characterized by excess adiposity and metabolic dysfunction, is associated with a higher risk of implantation failure, miscarriage, and other pregnancy complications. Although obesity has been linked to impaired endometrial biology and disrupted uterine function, how it influences developmental processes in the early pregnant endometrium remains poorly defined. The endometrium plays critical roles in pregnancy establishment, placentation, and fetal growth. Central to this process is decidualization, during which endometrial stromal cells differentiate into specialized decidual cells that regulate key processes such as trophoblast invasion, vascular remodeling, and immune adaptation. Given the broad impacts of maternal obesity on reproductive outcomes, understanding how obesity alters the cellular composition and transcriptome of the decidualizing endometrium is important for identifying diet-driven disruptions. In this thesis, I used a mouse model of maternal obesity in combination with single-cell RNA transcriptomics to examine the broad impact of obesity on the post-implantation endometrium. This high-resolution approach enables the simultaneous characterization of gene pathways and cell-cell interactions of multiple cell types within the endometrium. My analyses showed that obesity causes transcriptomic changes within key endometrial cell populations, including stromal and immune (i.e., natural killer cell, macrophage) cell subtypes. Single-cell RNA-seq inferred cell differentiation analyses showed that maternal obesity disrupts discrete stromal cell differentiation pathways, suggesting that obesity impairs early decidualization. Lastly, ligand-receptor interaction analyses revealed widespread alterations in stromal-immune cell communication, indicating that maternal obesity perturbs critical cross-talk between these important endometrial cell types. Together, these findings establish a comprehensive single-cell atlas of the post-implantation mouse endometrium and offer new insights into how maternal obesity shapes the establishment of the endometrium in early pregnancy. This atlas provides critical insight into specific endometrial processes affected by obesity and serves as a resource for future studies investigating the significance of these obesity-linked changes in impacting pregnancy and fetal health.