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Title

Early Pregnancy Loss: A Role For Glucose Utilization In The Endometrial Stroma

Date of Award

Spring 5-15-2013

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Recurrent pregnancy loss affects a large number of women, and the causes of this disorder remain largely unknown. One of the key steps in establishing a successful pregnancy is embryo implantation. While embryo abnormalities may certainly lead to pregnancy loss, it is equally important for the uterine endometrium to adequately progress to, what is termed, a receptive state. The endometrium is composed of several cell types, including the epithelial, stromal, endothelial and a number of resident immune cells. A hallmark of endometrial receptivity is the differentiation of the endometrial stromal cell (ESC) compartment into the decidua. During this process, termed decidualization, the ESCs undergo a number of morphological and functional changes, which results in their ability to support early embryo growth and development prior to full placental function. Decidual cells show evidence of drastic changes in glucose metabolism, which is evidenced by their high stores of glycogen granules. We, therefore, hypothesized that increased glucose uptake by ESCs is necessary for decidualization and that this excess glucose is differentially metabolized in the decidual cells versus undifferentiated stroma. We first explored the abundance of GLUT mRNAs in primary ESCs isolated from mice and humans. We found that GLUT1 mRNA is the most abundant among glucose transporter family members in the ESCs of both species studied, but several other transporters also show moderately high mRNA levels. We also determined that GLUT1 is required for proper decidualization of human ESCs since in vitro knockdown of this gene significantly lowered expression of the known decidualization markers, PRL and IGFBP1. Lastly, we also demonstrated that metabolism of glucose through the pentose phosphate pathway is a requirement for proliferation and decidualization of endometrial stroma. Inhibition of the pentose phosphate pathway led to a significant decrease in the decidual reaction both in vitro and in vivo. Taken together, the outcomes of this study highlight two distinct steps of glucose utilization, uptake via Glut1 and flux through the pentose phosphate pathway, which are both necessary for proper ESC decidualization. Abnormal glucose utilization by decidualizing ESCs may provide a mechanistic explanation for idiopathic recurrent pregnancy loss.

Language

English (en)

Chair and Committee

Kelle H Moley

Committee Members

Paul Goodfellow, Paul Hruz, Liang Ma, Michael Mueckler, Dwight Towler

Comments

Permanent URL: https://doi.org/10.7936/K7WS8R5M

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