Abstract
Early embryo miscarriage is linked to inadequate endometrial decidualization, a cellular transformation process that enables deep blastocyst invasion into the maternal compartment. Although much of the cellular events that underpin endometrial stromal cell (ESC) decidualization are well recognized, the individual gene(s) and molecular pathways that drive the initiation and progression of this process remain elusive. Using a genetic mouse model and a primary human ESC culture model, we demonstrate that steroid receptor coactivator-2 (SRC-2) is indispensable for rapid steroid hormone-dependent proliferation of ESCs, a critical cell-division step which precedes ESC terminal differentiation into decidual cells. We reveal that SRC-2 is required for increasing the glycolytic flux in human ESCs, which enables rapid proliferation to occur during the early stages of the decidualization program. Specifically, SRC-2 increases the glycolytic flux through induction of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3), a major rate-limiting glycolytic enzyme. Similarly, acute treatment of mice with a small molecule inhibitor of PFKFB3 significantly suppressed the ability of these animals to exhibit an endometrial decidual response. Together, these data strongly support a conserved mechanism of action by which SRC-2 accelerates the glycolytic flux through PFKFB3 induction to provide the necessary bioenergy and biomass to meet the demands of a high proliferation rate observed in ESCs prior to their differentiation into decidual cells. Because deregulation of endometrial SRC-2 expression has been associated with common gynecological disorders of reproductive-age women, this signaling pathway, involving SRC-2 and PFKFB3, promises to offer new clinical approaches in the diagnosis and/or treatment of a non-receptive uterus in patients presenting idiopathic infertility, recurrent early pregnancy loss, or increased time to pregnancy.
Highlights
Progression of embryo implantation into a receptive endometrium relies on endometrial stromal cells (ESCs) undergoing decidualization, a critical cellular transformation process which determines the depth of embryo invasion and placentation [1,2,3]
Advances in our understanding of oocyte and embryo development have significantly increased pregnancy success rates, these rates remain unacceptably low due in part to an endometrium that is unreceptive to embryo implantation
steroid receptor coactivator-2 (SRC-2) is critical for the metabolic reprogramming of the endometrium to a receptive state, which provides the pretext for considering this factor and its metabolic targets in the design of future clinical approaches to diagnose and therapeutically treat those women at a high risk for early pregnancy loss
Summary
Progression of embryo implantation into a receptive endometrium relies on endometrial stromal cells (ESCs) undergoing decidualization, a critical cellular transformation process which determines the depth of embryo invasion and placentation [1,2,3]. Inadequate decidualization of ESCs can lead to embryo miscarriage and early pregnancy loss irrespective of whether the development of the blastocyst is normal. The initial cellular events of embryo implantation in the human are interstitial as opposed to eccentric in the mouse [1], the fundamental developmental steps that lead to the establishment of the receptive uterus are common to both species, suggesting that many of the biochemical and molecular mechanisms underlying E2 and P4 control of these developmental steps are conserved.
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