(192) Loss of Glucose Transporter 1 in mouse endometrial stromal cells leads to dysregulation of trophoblast differentiation and placenta development

Ritwik Shukla¹, Kevin Porter¹, Cheyenne Summers¹, Athilakshmi Kannan¹, Arpita Bhurke¹, Milan K. Bagchi², and Indrani C. Bagchi¹

1. Departments of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL
2. Department of Molecular & Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL

Abstract Text:

The establishment and maintenance of pregnancy depend on a complex relationship between the uterus and the implanting embryo. This critical phase of reproduction begins when the embryo attaches to the uterine epithelium. Subsequently, the underlying stroma undergoes a significant transformation to become the decidua, which surrounds the developing fetus. Differentiated stromal cells, known as decidual cells, produce and release paracrine factors that regulate various functions within the pregnant uterus, including the development of an extensive vascular network essential for supporting embryonic growth. Additionally, the proper differentiation of trophoblast cells, which is crucial for the formation of a functional placenta, is influenced by maternal factors secreted by the decidual cells. The metabolic adaptations of decidual cells important for these physiological events are largely unknown. In this study, we observed that glucose transporter 1 (GLUT1) is expressed in decidual cells during implantation, and we demonstrated using a conditional knockout mouse model that it is essential for establishing and maintaining pregnancy. Mice lacking the Glut1 gene in uterine stromal cells are severely subfertile. The ablation of Glut1 did not impact the attachment of the embryo to the uterine epithelium; however, it resulted in impaired decidualization and angiogenesis. Defects in these processes during early pregnancy can perturb the uterine environment, which may lead to inadequate secretion of maternal factors essential for trophoblast differentiation. Indeed, we observed abnormal trophoblast giant cell and spongiotrophoblast differentiation and overall compromised placentation in mice lacking uterine Glut1. Notably, placental lactogen 1 (PL1), a hormone produced by trophoblast giant cells, is overexpressed, while placental lactogen 2 (PL2), which is synthesized by spongiotrophoblast cells, is significantly downregulated in placentas from Glut1 mutants. We suggest that these impairments in trophoblast differentiation led to placental dysfunction, which resulted in fetal loss in Glut1 mutants. This study identifies the crucial role of endometrial GLUT1 in regulating maternal metabolism and placentation during pregnancy.
[Supported by NIH R01 HD 090066]