Elsevier

Theriogenology

Volume 150, 1 July 2020, Pages 294-301
Theriogenology

Roadmap to pregnancy during the period of maternal recognition in the cow: Changes within the corpus luteum associated with luteal rescue

https://doi.org/10.1016/j.theriogenology.2020.01.074Get rights and content

Highlights

  • For pregnancy to be established, the corpus luteum must be maintained.

  • Controversy exists regarding the mechanisms by which the CL is maintained.

  • There are molecular and functional changes within the CL during the establishment of pregnancy.

  • The changes in the CL are consistent with activation of processes that protect the CL from regression.

Abstract

A viable corpus luteum (CL) producing an adequate amount of progesterone is absolutely essential for establishment and maintenance of pregnancy. One function of embryonic signaling to the mother is to ensure that the CL is maintained. In ruminants, the secretion of uterine prostaglandin F2alpha (PGF2A) is the signal that initiates luteolysis. Despite many studies to determine if PGF2A secretion from the uterus is altered in early pregnancy, conflicting interpretations have led to controversy regarding the exact mechanisms by which maternal recognition of pregnancy is achieved. In addition to alteration of uterine prostaglandin metabolism, changes within the CL itself may facilitate the establishment of a successful pregnancy. These changes include alteration of luteal blood flow, prostaglandin metabolism, sensitivity to prostaglandin actions, increased steroidogenic capacity, significant intracellular molecular changes and modification of the immune cells that are within the CL. Whether these intraluteal changes are necessary to establish pregnancy is undetermined. The focus of this review will be to provide a brief historical perspective on the utero-ovarian relationships that regulate luteal lifespan and review current knowledge of the CL of pregnancy in sheep and cattle.

Introduction

Pregnancy is the result of remarkably coordinated and carefully timed events that allow for development of an organism from two cells to a fully formed, functional individual. That gametogenesis, fertilization, and embryonic differentiation can all proceed without error is truly astonishing, and yet a successful pregnancy will be achieved only if the developing conceptus can elicit changes in its mother that nurture its development and prevent its rejection. A critical change that must occur in the mother is the prevention of luteolysis. A viable corpus luteum (CL) producing an adequate amount of progesterone is absolutely essential for establishment and maintenance of pregnancy. Progesterone regulates uterine prostaglandin production and those uterine functions that support the establishment of a pregnancy. Thus, one function of embryonic signaling to the mother is to ensure that the CL is maintained. Essentially, a symbiotic relationship exists between the CL and the embryo, because each requires the other in order to survive.

In a normal estrous or menstrual cycle, the absence of embryonic signaling results in regression of the CL, a process that allows for ovulation of a new follicle and another chance to establish a pregnancy. This process defines polycyclic species and is in contrast to the lack of a known luteolytic signal in monocyclic species, such as the dog, in which there is no subsequent ovulation. In ruminants, the secretion of uterine prostaglandin F2alpha (PGF2A) is the signal that initiates luteolysis, which is manifested as a rapid decrease in steroidogenesis and more gradual demise of the tissue itself. The requirement of the uterus for luteolysis and normal cyclicity was demonstrated in cattle and sheep by Wiltbank and Casida [1]. It was later discovered that the role of the uterus is to secrete PGF2A, which travels to the ovary and initiates luteal regression [reviewed in 2]. The focus of this review will be to provide a brief historical perspective on the utero-ovarian relationships that regulate luteal lifespan and review current knowledge of the CL of pregnancy in sheep and cattle.

In cattle and sheep, the requirement for the uterus to initiate luteolysis is undisputed [1], although the authors questioned if the maintained corpora lutea (CL) were functionally the same as the CL in pregnant animals. Progesterone was not measured in that study, but presumably the CL were secreting progesterone, because the return to estrus was delayed. Hysterectomy rescued induced CL in the postpartum cow that otherwise were destined to be short-lived, in which case both structure and progesterone production were maintained [3]. A series of experiments in cattle and sheep ultimately demonstrated that the uterine luteolysin in these species is PGF2A [reviewed in 4]. Suppression of PGF2A production by intrauterine infusions of indomethacin resulted in extension of luteal lifespan [5], as did passive [6] or active [7,8] immunization against PGF2A. However, in all of these studies, the observation periods were not sufficient to determine how long the maintained CL was viable.

Despite many studies in which prostaglandins were measured, controversy remains regarding prostaglandin concentrations to which the CL would be exposed during maternal recognition of pregnancy. Mezera et al. [9] collected bihourly jugular blood samples from nonbred and bred cattle on D 18 to 21 after estrus. Cows in which the CL regressed exhibited clear pulses of 15-keto-13,14-dihydroprostaglandin F2A (PGFM), a metabolite of PGF2A, whereas pregnant cows, or those with prolonged estrous cycles, lacked PGFM pulses at the expected time. Interestingly, PGFM increased again during the second month of pregnancy, providing evidence that regulation of uterine prostaglandin synthesis is not likely to be necessary for luteal maintenance after the period of maternal recognition of pregnancy (MRP). Wiltbank et al. [10] postulated that the increase in blood flow to the gravid uterine horn ipsilateral to the CL during the second month of pregnancy inhibits the local transport of PGF2A to the ovary. The lack of PGFM pulses in pregnant cows demonstrated by Mezera et al. [9] is in agreement with an earlier report of Betteridge et al. [11], in which a series of PGFM pulses was detected in the jugular blood of cows during luteolysis, whereas PGFM pulses were reduced or absent in the pregnant animals. Pinaffi et al. [12] recently reported that on D 16 to18 postovulation, frequency of PGFM pulses was similar in pregnant and cyclic heifers, but the mean concentration of PGFM was less in the pregnant animals. In cyclic heifers, there was a transient decrease in progesterone concentration starting 2 h before each PGFM peak and rebounding within 2 h after the peak, but decreases in progesterone did not occur in the pregnant animals, indicating a differential responsiveness of the CL to uterine PGF2A in the two groups [12]. Lukaszewska and Hansel [13] collected blood directly from the uterine vein of cyclic and pregnant cows on D18 and observed that concentrations of PGF2A were approximately two-fold greater in the uterine vein plasma of cyclic, compared to pregnant, cows, but progesterone had already begun to decline in the cyclic animals and was approximately two-fold less than in the pregnant cows, indicating that luteolysis had already been initiated.

Thorburn et al. [14] measured PGF2A in the uteroovarian venous plasma of ewes and reported periodic peaks of PGF2A in cyclic, but not pregnant ewes, although this study used only 2 ewes per group. Pexton et al. [15,16], Lewis et al. [17] and Silvia et al. [18] found no difference in concentrations of PGF2A in the uteroovarian vein of pregnant and nonpregnant ewes during the period of MRP. In fact, in both pregnant and cyclic animals, a similar increase in uteroovarian venous concentration of PGF2A over time was observed. The difference noted was that PGE2 concentrations were greater in pregnant than cyclic ewes, supporting the hypothesis that PGE2 may play a role in maintenance of the CL in early pregnancy [18]. This was supported by the work of Lee et al. [19], who observed that during maternal recognition of pregnancy (D 16) in sheep, there was a shift in uterine secretion of PGF2A into the lumen rather than into the uterine vein, but there were greater concentrations of PGE2 in the uterine vein and the ovarian artery on D 16 of pregnancy compared with that of the estrous cycle.

Some have questioned if the jugular concentration of PGFM accurately reflects the PGF2A concentration that may reach the CL, either through local counter-current transfer or through the systemic circulation. Peripheral concentrations of PGFM reflect not only uterine secretion of PGF2A, but production or metabolism of PGF2A by many tissues. To address this question in cows, Inskeep and colleagues cannulated the posterior vena cava via the coccygeal vein to measure uterine and ovarian release of PGF2A and PGFM, and compared this to PGFM concentrations in the jugular vein. Hourly blood samples were collected for 48 h on D16 and 17, for 12 h on D 19, and for 6 h on D 20. Concentrations of PGF2A in the vena cava were greater and more variable than concentrations of PGFM in the jugular vein. The mean concentration of PGFM in the jugular vein, but not that of PGF2A in the vena cava, increased on D 19 compared to D 16 and 17, perhaps due to altered metabolism of PGF2A near the end of the cycle. Most interestingly, neither the means nor variances of PGFM, in either the jugular vein or vena cava, were correlated to the means or variances of PGF2A in the vena cava [20]. However, Ochoa et al. [21] infused exogenous PGF2A and PGE1 into the uterus and found that PGFM and PGEM in the blood accurately reflected PGF2A and PGE1 infused into the uterus.

Although Lukaszewska and Hansel [13] measured greater concentrations of PGF2A in the uterine vein of cyclic animals, the concentrations of PGF2A in the ovarian artery did not differ from those in pregnant animals, suggesting that either counter-current transfer of the PGF2A was altered, or that metabolism of the PGF2A was greater in the cyclic animals. The notion that differences in the above studies might be due to local and peripheral metabolism of PGF2A has not been explored. In sheep, approximately 99% of PGF2A was metabolized to PGFM during the first passage through the lungs [22], but in cattle, after one passage through the lungs, 35% of PGF2A remained. Of the 65% that was metabolized, 32% was detected as PGFM and two other unidentified metabolites comprised 33% [23]. Because a lesser proportion of PGF2A is rapidly metabolized in cows compared to sheep, the possibility exists that luteolysis may be at least partially mediated by PGF2A that is not transferred locally from the uterus to the ovary. Hansel and Fortune [24] presented an argument that local counter current transfer of PGF2A from the uterus to the ovary is complemented by other mechanisms that facilitate luteolysis in cows. One of the very intriguing findings was that hysterectomized heifers were more sensitive to the luteolytic effect of a low concentration of injected PGF2A than uterine intact heifers, exactly opposite of what one might predict. When considered in light of the work of Silvia et al. [18] showing increased uterine secretion of PGE2 in pregnant compared to cyclic ewes, and the decreased sensitivity of the CL of pregnancy to PGF2A [12,[25], [26], [27]], it is tempting to speculate that in Hansel and Fortune's uterine-intact heifers, the CL was protected from PGF2A effects by PGE2 secreted from the uterus, whereas the hysterectomized heifers lacked uterine PGE2 to provide luteotropic support and counteract the luteolytic effect of PGF2A. Intraluteal injection or intrauterine infusion of PGE1 or PGE2 [25, reviewed in 28] in sheep delayed luteolysis, and intrauterine infusion of PGE1 in cows conferred a luteoprotective effect, inhibiting the actions of simultaneously infused PGF2A [21].

Fredricksson et al. [29] detected large pulses of PGFM and the 11-ketotetranor metabolites in the jugular samples of goats at the end of the estrous cycle, but the large pulses were absent during pregnancy. However, while baseline PGFM remained low throughout early pregnancy, baseline concentrations of 11-ketotetranor PGF were the same or greater than in the preceding estrous cycle. Similar results were reported for sheep, in which pregnant ewes had greater basal concentrations of PGFM on D 13-17, but fewer PGFM pulses than cyclic ewes [30]. The 11-ketotetranor metabolite of PGF2A was not different in the two groups, except on D14, when the mean and basal concentrations were greater in the pregnant ewes. This supported earlier work [31] in which it was concluded that maintenance of the CL in sheep depends on reduction in the pulsatile secretion of PGF2A, but these data may be consistent with an effect of pregnancy on metabolism of PGF2A.

Clearly, even in the absence of an embryo, the lifespan and function of the ruminant CL can be extended by removal of the uterus or the PGF2A that it produces, but during early pregnancy, the CL is exposed to embryonic and uterine signals that could elicit changes in the CL itself. Lukaszewska and Hansel [13] reported that pregnant heifers had greater concentrations of plasma progesterone than cyclic or bred, nonpregnant heifers between D 10 to 18 after estrus. It is unknown if this was due to the presence of an embryo or if it was the reason the pregnancy was maintained, but in the open cows progesterone concentrations were between 4 and 5 ng/ml, which should have been sufficient to maintain a pregnancy in nonlactating heifers. Greater concentrations of progesterone after insemination are associated with higher pregnancy rates in lactating cows [32,33]. Wickersham and Tanabe [34] compared CL collected from heifers on D 14 of the estrous cycle and D 28 of pregnancy. Although there was no difference in luteal weight, both luteal progesterone content and de novo synthesis of progesterone in vitro were significantly greater in the D 28 CL, showing that the steroidogenic capacity of the CL per unit weight of tissue increased during early pregnancy. Furthermore, CL that were collected from ewes with healthy embryos secreted more progesterone in vitro than when CL came from ewes with abnormal or no embryos [35]. Any changes in the CL that enhance steroidogenic capacity may lead to increased likelihood of successful pregnancy.

As discussed above, although the pattern of PGF2A secretion from the uterus may be altered in early pregnancy, the mean concentration of PGF2A in the vena cava [20] or in the ovarian artery [13] did not differ in cyclic and pregnant cows. Maintenance of the CL, even in the presence of PGF2A, may be facilitated by the decreased sensitivity of the CL of pregnancy to the luteolytic effects of PGF2A [25,26], perhaps facilitated by PGE2, as discussed above [21,25], but the refractoriness to PGF2A is transient; sensitivity of the CL to PGF2A returns about D 19 in sheep [27]. Conceptus secretory proteins also increase progesterone production and reverse the inhibitory effects of PGF2A on steroidogenesis by luteal cells in vitro [36]. In cows and sheep, the conceptus secretes interferon tau (IFNT) that acts in the uterus to alter prostaglandin production (reviewed in 37, 2), but IFNT also enters the maternal circulation [38] and increases interferon-stimulated genes in the CL [[38], [39], [40], [41], [42], [43]], providing evidence for a direct effect of embryonic secretions on the CL. Interferon-stimulated genes are upregulated in cultured bovine luteal cells that are treated with IFNT, with no direct effect on progesterone production, but IFNT-treated polymorphonuclear cells cocultured with luteal cells promoted progesterone production [44]. Additionally, cultured bovine luteal cells treated with IFNA, which acts through the same receptor as IFNT, are protected from cytokine-induced prostaglandin production and cell death [45,46]. Basavaraja et al. [47] used luteinized bovine granulosal cells as a model for large luteal cells, and observed that IFNT enhanced cellular viability by upregulating cellular survival genes and reducing the mRNA for proteins that mediate apopotosis; it also increased mRNA involved in angiogenesis and promoted endothelial cell survival [48]. Notably, IFNT was able to reverse the ‘luteolytic’ actions of thrombospondin 1 on these cells. Finally, direct effects of IFNT on cultured luteal endothelial cells, such as increased cellular proliferation [48], are consistent with increased blood flow observed in the CL of pregnancy compared to that of the cycle [49,50]. Abundance of endothelial cell mRNA that are important in luteolysis is also reduced by IFNT [48].

When the CL of pregnancy and the CL of the cycle are compared during MRP, there are differences in abundance of molecular mediators of luteal function. In early studies to explore the possibility of immune cell activation in luteolysis, Benyo et al. [51] used flow cytometry of freshly dissociated luteal cells and showed that subpopulations of cells expressed class II major histocompatibility (MHC) molecules and that the proportion of cells expressing class II MHC was less in the D 18 CL of pregnancy compared to that of the cycle. Reduced expression of class II MHC in early pregnancy also was observed in ovine [52] and equine [53] luteal cells. Luteal cells that express class II MHC molecules activate T lymphocytes [54], so suppression of class II MHC molecule expression during early pregnancy may alter the nature of cellular interactions within the CL that allow immune cells to facilitate either luteolysis or luteal rescue. Expression of class II MHC molecules is induced on luteal cells by IFNG [55], but this induction is reduced by IFNA [56], which signals through the same Type I IFN receptor as IFNT. These data provided the early evidence that rescue of the CL during maternal recognition of pregnancy involved regulation of immune response mechanisms. The possibility exists that early pulses of PGF2A from the uterus of the cyclic animals caused the increase in luteal MHC molecules, but there is no evidence that PGF2A directly induces class II MHC expression. An alternative possibility is that embryonic signaling resulted in changes in the CL that suppressed class II MHC expression. This raised the intriguing possibility that the CL wasn't simply maintained by differential secretion of PGF2A in early pregnancy, but that changes occur within the CL itself, perhaps to further ensure its survival and maximal steroidogenic potential.

Lymphocytes and macrophages infiltrate the bovine CL about estrous cycle D 14 and D 19, respectively, but fewer of these immune cells are present in the CL of pregnancy [57]. However, there is a transient influx of neutrophils into the CL during maternal recognition of pregnancy [44]. When T lymphocytes in the D 18 CL of pregnancy and the estrous cycle were compared, it was observed that the proportion of T lymphocytes that were CD8+ was nearly doubled in the CL of pregnancy, and the γδ+CD8+ cells more than doubled [58]. γδ+CD8+ cells express genes that are involved in promoting quiescence [59], perhaps creating a local environment more conducive to luteal cell survival. These differences were not observed in peripheral (blood) T lymphocytes, showing that the effect of pregnancy on those cells was specific to the cells that were residing within the CL. Interferon tau stimulated expansion of γδ+CD8+ lymphocytes and inhibited the proinflammatory type of γδ+CD8+ cells in vitro [60]. Together, these data provide evidence that embryonic secretion of IFNT may directly alter the functional properties of immune cells within the CL during maternal recognition of pregnancy.

Atli et al. [61] infused PGF2A into the uterus of cows at a dose and rate that resulted in luteolysis in only half of the animals. Comparison of mRNA abundance in those CL that were maintained to those that regressed revealed that activation of immune response genes is a major component of luteolysis, but those genes were not activated in the maintained CL. Therefore, even in the absence of embryonic signaling, CL that are maintained can be distinguished from those that regress by lack of activation of immune response genes, demonstrating the importance of regulation of immune cells for luteal survival. Other mRNA that differed in that study showed that an increase in the prostaglandin synthesis pathway and a decrease in prostaglandin catabolism occurred in the CL that regressed, whereas these pathways did not change in the CL that were maintained. This supports previous work demonstrating that at least two mechanisms exist to reduce luteal concentrations of PGF2A during early pregnancy. The first is to prevent luteal synthesis of PGF2A and increase the PGE to PGF ratio [62], and the second is to increase catabolism of PGF2A by upregulation of the activity of 15-hydroxy-prostaglandin dehydrogenase [63]. These changes are important, because luteal prostaglandin synthesis is necessary for luteal regression in sheep [64].

Considering that changes may occur within the CL to ensure its survival, it was hypothesized that alteration of microRNA (miRNA) expression may serve as a ‘molecular switch’ to regulate synthesis of proteins important for luteal survival. To that end, deep sequencing was employed to profile miRNA in CL on D 17 of the estrous cycle or pregnancy. In the analysis using the database available at that time, and a stringent false discovery rate correction, 12 miRNA were found to be differentially abundant. Functional pathway analysis of the predicted targets of these miRNA demonstrated that they were highly likely to be involved in immune response processes, eg. T cell receptor signaling, PKCθ signaling in T cells and role of macrophages, as well as regulation of apoptosis, calcium signaling and response to interferon-gamma, all of which are involved in luteolysis [65]. From the same tissues, mRNA and proteins were profiled, and the results integrated with the differentially abundant miRNA [66]. This analysis indicated that in early pregnancy, changes in luteal miRNA likely regulate pathways related to extracellular matrix and cellular metabolism. More compelling results were obtained from the independent analyses of the differentially abundant mRNA and proteins. Three different programs were used in the analysis of mRNA to determine the pathways that are regulated in the D 17 CL. The two pathways common to all 3 programs were TGFB signaling and T cell activation and signaling. These data support previous studies showing that the fate of the CL is intricately tied to regulation of the immune cells within the tissue. Pathways predicted to be important in this fate decision, based on the differentially abundant mRNA, are depicted in Fig. 1. Perhaps most exciting, two mRNA that were less in the CL of pregnancy were regulated by PGF2A in cultured luteal cells, whereas two mRNA that were greater in pregnancy were directly regulated by IFNT, providing indirect evidence that the greater abundance of these mRNA in early pregnancy is due to IFNT signaling within the CL. Protein analysis also demonstrated a role for immune cell signaling in luteal fate, but additionally pointed to regulation of steroidogenesis and cholesterol biosynthesis (Fig. 2) [66], perhaps supporting those aforementioned studies in which the CL of pregnancy had a greater steroidogenic capacity than the CL of the cycle.

In those studies in which CL from cyclic and pregnant animals were compared at only one time, particularly just before the onset of luteolysis, it is impossible to know if differences in abundance of molecules are due to the action of PGF2A on the CL that will soon regress or to changes elicited by embryonic signaling. Romero et al. [42] evaluated mRNA abundance in ovine CL on D 12 and 14 of the estrous cycle and pregnancy. As early as D 12, 55 transcripts were differentially abundant in cyclic compared to pregnant ewes, and 21 transcripts changed between D 12 and D 14 of pregnancy. Pathways associated with these mRNA were immune response, IFN signaling, steroid biosynthesis and cytoskeletal remodeling. We conducted a study in which bovine CL were collected on days 14, 17, 20 and 23 of confirmed pregnancy. Day 14 was used to represent a baseline state, prior to known exposure of the CL to embryonic signals, essentially similar to a cyclic CL. On D 17, only the very earliest and probably low concentrations of IFNT might reach the CL, whereas by D 20 and 23 any potential changes in the CL due to IFNT or other embryonic or uterine sources should be observed. Cluster analysis was used to group mRNA and miRNA by pattern of expression. Of the mRNA that increased during early pregnancy, many are regulated by type I interferons, such as IFNT, whereas the clusters of mRNA that exhibited a temporal decline were not interferon-regulated genes, and were associated with PGF2A response in cells. Additional transcripts increased between D 17-20, but then declined, and were associated with immune cell functions. Furthermore, miRNA that target steroidogenesis and fatty acid degradation exhibited a temporal decline, perhaps allowing an increase in these functions in early pregnancy. Conversely, miRNA that increased during early pregnancy target pathways important in luteolysis, such as phosphatidylinositol signaling and fatty acid biosynthesis [67].

In studies from various laboratories, differences in CL of pregnancy and CL of the estrous cycle have been observed. Magata et al. [68] compared selected mRNA in bovine CL from D 29 to 33 of pregnancy to midcycle (D 10 to 13) CL. None of the mRNA measured by qPCR were less abundant in the CL of pregnancy, but genes associated with steroidogenesis, prostaglandin synthesis and immune response were in greater abundance in the CL of pregnancy. There was also greater abundance of mRNA for VEGFR3, a growth factor that stimulated lymphangiogenesis. This supports earlier work from this group showing that lymphangiogenesis occurred in the bovine CL of early pregnancy, due to upregulation of VEGFR3, which is stimulated by IFNT [69]. In early pregnancy (D 20 to 25), the bovine CL contains a greater abundance of mRNA and protein related to PGE synthesis, but less oxytocin, whereas in later pregnancy (D150 to 160) there is an increase in the chemokines eotaxin and lymphotactin [70,71]. Analysis of mRNA abundance in bovine CL also indicated that there may be activation of cellular survival pathways in the CL of pregnancy compared to that of the cycle [72]. Recently, there has been renewed interest in the role of lipids as regulators of luteal function. Hughes et al. [73] compared a panel of lipids in D18 CL of pregnancy and the cycle and found one lipid, 15-KETE, to be less abundant in the CL of pregnancy, although four other lipids tended to be less. Integration of these five lipids with the mRNA profiled in the D17 CL described above [66] indicated a role in immune cell chemotaxis and cell-cell communication. Further, three of the five lipids that were different or tended to be different on D18 also decreased when D18 CL of pregnancy were compared to D 11 of the estrous cycle, indicating that they may be downregulated during early pregnancy [73]. In a similar study of CL from cyclic and pregnant cattle on D 16, three different lipids varied, and pathway analysis indicated potential roles in cellular proliferation and vasodilation [74]. It is difficult to reconcile differences between these two studies, which could be due to day of tissue collection, handling of tissue or most importantly, diet of the animals, among other factors. It should be noted that in both studies, large variations in lipid concentrations were reported. There will likely be expanded research on lipid regulators of luteal function in the near future, and it may be very important for researchers to carefully control diet and other factors that can alter lipid concentrations and metabolism in the animals, and perhaps increase sample size to limit the effect of animal to animal variation.

Section snippets

Conclusions

Perhaps the most impactful discoveries in the field of ruminant reproduction in the last half of the 20th century were 1) the uterus is essential for luteolysis to occur at the end of the estrous cycle, 2) the luteolytic agent secreted from the uterus is PGF2A, and 3) prevention of luteolysis in early pregnancy is the result of IFNT secretion from the embryo. There is compelling evidence that in early pregnancy, there is a reduction in uterine secretion of PGF2A, especially as measured as one

Funding

Funding for the author was provided by Agriculture and Food Research Initiative Competitive Grant no. 2016-67015-24900 from the USDA National Institute of Food and Agriculture, Multistate Project NE 1727, and the C. Lee Rumberger and Family Chair in Agricultural Sciences Endowment.

Declaration of competing interest

The authors declare that they have no competing interests.

Acknowledgements

Thank you to Dr. Camilla Hughes for reading this review and providing valuable insight. I am grateful to Drs. E. Keith Inskeep and Milo Wiltbank for challenging my assumptions and providing fodder for thinking about what happens in the CL during its rescue from death.

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