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Review
. 2022 Jul 1;100(7):skac123.
doi: 10.1093/jas/skac123.

Ruminant conceptus-maternal interactions: interferon-tau and beyond

Daniel J Mathew  1 , Katie D Peterson  1 , L Kirsten Senn  1 , Mary A Oliver  2 , Alan D Ealy  2
Affiliations
Review

Ruminant conceptus-maternal interactions: interferon-tau and beyond

Daniel J Mathew et al. J Anim Sci. .

Abstract

Embryonic or fetal loss in cattle is associated with problems that occur during oocyte maturation, early embryonic development, conceptus elongation, maternal recognition of pregnancy (MRP), and/or placental attachment and implantation. Many of these problems manifest as inadequate or asynchronous communication between the developing conceptus and endometrium, resulting in pregnancy failure. This review will provide an overview of how various conceptus-endometrial paracrine signaling systems control the fate of early pregnancy in cattle and other ruminants. We begin by summarizing the actions of interferon-tau, the classic MRP signal in ruminates, and then explore how other secretory factors derived from either the conceptus or endometrium influence establishment and maintenance of pregnancy. Insight into how the endometrium responds to male vs. female conceptuses or conceptuses produced by in vitro methods will also be described. Specific focus will be placed on describing how "omic" technologies and other cutting-edge techniques have assisted with identifying novel conceptus and/or endometrial factors and their functions. Recent findings indicate that the endometrial transcriptome and histotroph are altered by conceptus sex, quality, and origin, suggesting that the endometrium is a sensor of conceptus biochemistry. Although the endometrium has a certain level of flexibility in terms of conceptus-maternal interactions, this interplay is not sufficient to retain some pregnancies. However, new information inspires us to learn more and will help develop technologies that mitigate early embryonic loss and reproductive failure in ruminants and other animals.

Keywords: bovine; embryo; endometrium; ovine; pregnancy; transcriptomics.

Plain language summary

Early pregnancy losses are common in cattle. This review describes how critical the interplay between the developing conceptus (embryo and extraembryonic membranes) and endometrium is to maintaining pregnancies in cattle and other ruminants. The discovery of interferon-tau more than 40 yr ago initiated a new field of reproductive biology focused on describing how the conceptus and endometrium communicate with one another through the secretion of paracrine factors, extracellular vesicles, and other molecules. The use of “omic” and gene editing technologies has assisted with identifying novel functions for many conceptus and endometrial secreted factors. This review provides examples of how conceptus sex, quality, and in vitro vs. in vivo development influences endometrial function. The endometrium appears to have some flexibility in its response to conceptuses, and this insight could be used to our advantage as we work towards developing schemes to rescue conceptuses that are in danger of experiencing pregnancy loss.

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Figures

Figure 1.
Figure 1.
Development of the bovine conceptus and fetus between days 2 and 120 of gestation. (a) A 2- and 3-celled embryo collected on day 2 of development. (b) Zona enclosed blastocyst with visible inner cell mass (ICM) and outer trophectoderm (TE) layer. (c) Day 13 ovoid conceptus with visible embryonic disc (ED). (d) Elongating day 15 conceptus with ED (subset image). (e) Elongated day 20 conceptus. The embryo, with a clear neural grove (NG), was dissected out of placental tissues (subset image). (f) Day 25 placental tissues and embryo (subset image) with developing eye and limb buds. (g) Day 40 placental tissues and embryo dissected away from the amniotic sac (subset). (h) Day 70 placental tissues, fetus, and uterus with clearly visible placental cotyledons and uterine caruncles. (i) A 4-mo-old fetus still within the uterus and placental amnion. The placentomes have been peeled apart to show the enlarged placental cotyledons and honeycomb appearance of the uterine caruncles.
Figure 2.
Figure 2.
The bovine conceptus microenvironment. (a and b) Image of a bovine uterus during the mid-luteal phase of the estrous cycle and depiction of an elongating conceptus within the uterine horn between days 13 and 15 of development. Caruncles (CAR) are visible along the uterine surface. (c) The critical period for maternal recognition of pregnancy (MRP) is between days 15 and 16 of development in cattle when the conceptus will secrete IFNT, the MRP signal, and other conceptus secretory factors (CSF) including extracellular vesicles (EV), bovine endogenous retroviral (BERV) particles, prostaglandins (PG), and over 1000 other proteins including interleukin-6 (IL-6), pregnancy-associated glycoproteins (PAG), and galectins (lectin, galactoside-binding, soluble; LGALS) (Brooks et al., 2014; Forde et al., 2015; Burns et al., 2016). The CSF modify expression of conceptus induced genes (CIG) within the endometrium, both dependent and independent of IFNT signaling. Conceptus-induced biological processes (CIBP) associated with upregulated IFNT independent genes are related to cilium activity, DNA repair, “chemokine production,” and the “inflammatory response” (Mathew et al., 2019). CIBP associated with downregulated genes are associated with “response to wounding,” “extracellular matrix repair,” and “cell migration and adhesion” (Mathew et al., 2019). (d) By day 30 of gestation, the mononuclear (MNT) trophoblast cells have migrated into CAR crypts where binucleate trophoblast cells (BNC) appear, sometimes fusing with the maternal luminal epithelial (LE) cells forming trinucleate cells (TNC). The BNC secrete PAG, placental lactogen (PL), and other hormones that enter maternal circulation. Overtime, vascularization of chorionic villi within endometrial crypts results in formation of placental cotyledons, that, together with the CAR, form placentomes, areas of maternal-fetal nutrient and waste exchange. Blood vessels (BV), glandular epithelium (GE), conceptus (cEV) and endometrial extracellular vesicles (eEV), immune cells (IC), trophectoderm (TE), embryonic disc (ED), and intercaruncular endometrium (ICAR).
Figure 3.
Figure 3.
Effect of conceptus origin and sex on the endometrial transcriptome. (a) Day 15, in vitro fertilization (IVF) derived, bovine conceptuses modified expression 83 genes within endometrium that were not modified by day 15 in vivo derived (artificial insemination; AI) bovine conceptuses (Mathew et al., 2019). IVF conceptus induced biological processes (IVF-CIBP) associated with upregulated genes included “response to wounding,” “unfolded protein response,” and “regulation of mRNA stability.” IVF-CIBP associated with downregulated genes included “calcium dependent exocytosis” and “endothelial cell migration.” (b and c) Endometrial gene expression was also modified by day 15 conceptus sex. (b) Day 15 female (XX) bovine conceptuses modified expression of 251 genes (XX conceptus-induced genes; XX-CIG) within the endometrium that were not modified by male conceptuses. Top XX-CIBP associated with up and downregulated genes were related to the immune response including “antigen presentation via MHC class I” and “chemokine production” (both upregulated) and “B-cell differentiation” (downregulated). (c) Day 15 male (XY) bovine conceptuses modified expression of 76 genes (XY conceptus-induced genes; XY-CIG) within the endometrium that were not modified by female conceptuses. No biological processes were associated with the upregulated XY-CIG; however, five biological processes were associated with the downregulated genes including “transmembrane transport,” “cell migration,” and “monocarboxylic acid transport.” Blood vessels (BV), luminal epithelium (LE), glandular epithelium (GE), conceptus (cEV) and endometrial extracellular vesicles (eEV), immune cells (IC), trophectoderm (TE), embryonic disc (ED), and caruncular endometrium (CAR).
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