Novel pathways for implantation and establishment and maintenance of pregnancy in mammals

Abstract

Uterine receptivity to implantation varies among species, and involves changes in expression of genes that are coordinate with attachment of trophectoderm to uterine lumenal and superficial glandular epithelia, modification of phenotype of uterine stromal cells, silencing of receptors for progesterone and estrogen, suppression of genes for immune recognition, alterations in membrane permeability to enhance conceptus-maternal exchange of factors, angiogenesis and vasculogenesis, increased vascularity of the endometrium, activation of genes for transport of nutrients into the uterine lumen, and enhanced signaling for pregnancy recognition. Differential expression of genes by uterine epithelial and stromal cells in response to progesterone, glucocorticoids, prostaglandins and interferons may influence uterine receptivity to implantation in mammals. Uterine receptivity to implantation is progesterone-dependent; however, implantation is preceded by loss of expression of receptors for progesterone (PGR) so that progesterone most likely acts via PGR-positive stromal cells throughout pregnancy. Endogenous retroviruses expressed by the uterus and/or blastocyst also affect implantation and placentation in various species. Understanding the roles of the variety of hormones, growth factors and endogenous retroviral proteins in uterine receptivity for implantation is essential to enhancing reproductive health and fertility in humans and domestic animals.

Figure 1

Hypothesis on the biological role of endogenous retroviruses (enJSRVs) Env and HYAL2 in trophoblast differentiation in sheep. Blastocyst growth from a spherical to an ovoid form occurs between Days 9 and 11 after hatching from the zona pellucida on Day 8 in sheep. Beginning on Day 12 of pregnancy, enJSRVs are expressed in the mononuclear trophectoderm cells (MTC) that begin to migrate and proliferate rapidly to support conceptus elongation and outgrowth (Step 1). By Day 14, some of the MTC begin to differentiate into trophoblast giant binucleate cells (BNC) (Step 2). Results interpreted exclusively from microscopy studies support the idea that trophoblast giant BNC are derived from karyokinesis without cytokinesis (endoreduplication). The inception of BNC differentiation coincides with the onset of HYAL2 expression in the BNC of the conceptus. The newly differentiated BNC begin to migrate and fuse with the endometrial luminal epithelial (LE) cells, forming a trinucleate cell (Step 3). During this period, the trophoblast giant BNC and endometrial LE cells express enJSRVs env RNA, whereas only the BNC express HYAL2. In fact, HYAL2 is not detected in any uterine cell type. Thus, the fusion of placental BNC and LE cells is hypothesized to involve enJSRVs Env and HYAL2. By Days 20 to 25, virtually all of the endometrial LE cells are fused with the BNC. During most of gestation, the BNC continue to differentiate from the MTC and then fuse with each other to form multinucleated syncytial plaques with 20–25 nuclei (Step 4). The trophoblast giant BNC and multinucleated syncytia line the cotyledons of the placenta that interdigitate with the endometrial caruncles to form the placentomes, which is necessary for hematotrophic nutrition of the fetus.