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. 2018 Aug 3;15(Suppl 1):843-855.
doi: 10.21451/1984-3143-AR2018-0014. eCollection 2018 Jul-Sep.

Cellular events during ovine implantation and impact for gestation

Greg A Johnson  1 , Fuller W Bazer  2 , Robert C Burghardt  1 , Guoyao Wu  2 , Heewon Seo  1 , Avery C Kramer  1 , Bryan A McLendon  1
Affiliations

Cellular events during ovine implantation and impact for gestation

Greg A Johnson et al. Anim Reprod. .

Abstract

The establishment of pregnancy in sheep includes elongation of the blastocyst into a filamentous conceptus, pregnancy recognition, production of histotroph, attachment of the conceptus to the endometrium for implantation, and development of synepitheliochorial placentation. These processes are complex, and this review describes some of the molecular events that underlie and support successful pregnancy. The free-floating sheep blastocyst elongates into a filamentous conceptus and metabolizes, or is responsive to, molecules supplied by the endometrium as histotroph. Amongst these molecules are SPP1, glucose and fructose, and arginine that stimulate the MTOR nutrient sensing system. The placental trophectoderm of elongating conceptuses initiate pregnancy recognition and implantation. The mononucleate cells of the trophectoderm secrete IFNT, which acts on the endometrial LE to block increases in estrogen receptor α to preclude oxytocin receptor expression, thereby preventing oxytocin from inducing luteolytic pulses of PGF2α. In addition, IFNT increases expression of IFN stimulated genes in the endometrial stroma, including ISG15, a functional ubiquitin homologue. Implantation is the initial step in placentation, and includes sequential pre-contact, apposition, and adhesion phases. Implantation in sheep includes downregulation of Muc1 and interaction of GLYCAM1, galectin 15 (LGALS15) and SPP1 with lectins and integrins (αvβ3). Sheep have synepitheliochorial placentation in which mononucleate trophectoderm cells fuse to form binucleate cells (BNCs). BNCs migrate and fuse with endometrial LE cells to form trinucleate syncytial cells, and these syncytia enlarge through continued BNC fusion to form syncytial plaques that form the interface between endometrial and placental tissues within the placentome. The placentae of sheep organize into placentomal and interplacentomal regions. In placentomes there is extensive interdigitation of endometrial and placental tissues to provide hemotrophic nutrition to the fetus. In interplacentomal regions there is epitheliochorial attachment of endometrial LE to trophectoderm, mediated through focal adhesion assembly, and areolae that take up histotroph secreted by endometrial GE.

Keywords: conceptus; endometrium; placentation; pregnancy; sheep..

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Figures

Figure 1
Figure 1. Elongation of the blastocyst into a filamentous conceptus. Sheep embryos enter the uterus at about day 3 or 4, develop into spherical blastocysts and then, after hatching from the zona pellucida, transform from spherical to tubular and filamentous conceptuses (embryos and associated placental membranes) between days 12 and 15 of pregnancy, with placental membranes extending into the contralateral uterine horn between days 16 and 20 (Bazer et al., 2005). Conceptus elongation ensures maximum area of surface contact between the conceptus trophectoderm and endometrial luminal epithelium (LE).
Figure 2
Figure 2. Pregnancy recognition, production of histotroph, and induction of classical IFN-stimulated genes. A) Generalized diagram of paracrine effects between the conceptus (primarily the pregnancy recognition signal IFNT) and the endometrium. B) Model for pregnancy recognition in the sheep in which IFNT silences expression of estrogen receptor α and this prevents expression of estrogen dependent expression of oxytocin receptor. C) Hematoxylin and Eosin (H&E) staining illustrating protein (histotroph) in the endometrial lumen of a pregnant sheep. D) In situ hybridization illustrating the expression of IFNT by conceptus trophectoderm and induction of ISG15 in the endometrium.
Figure 3
Figure 3. Attachment cascade of the conceptus to the endometrium for implantation. A generalized diagram of implantation in epitheliochorial and synepitheliochorial species. Implantation in sheep extends from days 11-16 and includes four phases that overlap and involve increasingly complex interactions between conceptus trophectoderm and endometrial luminal epithelium (LE). The inserted picture depicts immunostaining of proliferating trophectoderm cells (green color) at an implantation site. The current consensus for the attachment cascade in sheep includes downregulation of mucin 1 (MUC1) across the entire endometrial surface, which unmasks glycosylation dependent cell adhesion molecule 1 (GLYCAM1), galectin-15 and SPP1 for interaction with lectins and integrins. Initial attachment is likely mediated by GLYCAM1 and LGALS15, and firm attachment is likely mediated by SPP1 and the αvβ3 integrin receptor (Spencer et al., 2004).
Figure 4
Figure 4. Syncytialization at the uterine-placental interface of sheep (Wooding et al., 1984; Wooding and Burton, 2008). Illustrated are a cartoon of the current consensus for syncytia formation in the sheep and immunofluorescence staining for pregnancy associated glycoprotein (PAG; Szafranska et al., 1995); stains BNCs, TNCs and syncytial plaques green) and CDH1 (epithelial cadherin (E-Cad); stains mononuclear Tr and endometrial LE cells red).
Figure 5
Figure 5. The endometrial-placental interface of mature placentation in the sheep illustrating the placentome and the areola. Illustrated are cartoons depicting the structure of the sheep placentome (Top Left) and areola (Top Right), and H&E staining of a paraffin embedded thin section of a placentome (Bottom Left) and an areola (Bottom Right).
Figure 6
Figure 6. Focal Adhesions at the endometrial-placental interface of interplacentomal regions of placentation in the sheep (Burghardt et al., 2009). Illustrated is immunofluorescence staining (Top Panel) for αv integrin and a cartoon (Bottom Panel) depicting the localization of the focal adhesions that form at the interface between endometrial LE cells and the chorion.
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