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Cancer and Developmental Biology Laboratory (J.R.C., J.-G.C., L.H., C.L.S.), ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702; Science Applications International Corporation (T.S., L.S.), NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201
Address all correspondence and requests for reprints to: Colin L. Stewart, Laboratory of Cancer and Developmental Biology, National Cancer Institute-FCRDC, P.O. Box B, Frederick, Maryland 21702-1201. E-mail: stewartc{at}mail.ncifcrf.gov
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In preparation for implantation, the uterine tissues undergo distinct cycles of cell proliferation and differentiation. These are induced by the ovarian steroid hormones estrogen (E2) and progesterone (P4) (2, 3, 4, 5). Some of these changes are either directly mediated by the action of the hormones on the cells or are indirectly regulated through the induction of locally produced growth factors and cytokines, such as epidermal growth factor (EGF) (6, 7), and insulin-like growth factor 1 (IGF-1) (8, 9).
In conjunction with these cycles, the uterus undergoes a change in its receptivity. In mice, blastocysts cannot implant during the first 3 days following mating. Late on the fourth day until early on the fifth day, for about 18 h the uterus becomes receptive (10). At the onset of this period, the blastocysts are in close contact (apposition) with the luminal epithelium. With the start of implantation, the luminal epithelium adjacent to the mural trophectoderm undergoes apoptosis and the trophoblast cells migrate into the underlying endometrial stroma (11). The stroma responds by rapidly proliferating and differentiating to form the decidua. If implantation doesn’t occur, the uterus becomes nonreceptive, refractory to implantation, and eventually re-enters the reproductive cycle.
In rodents, implantation is stimulated by a transient rise in circulating levels of E2—the nidatory surge on the morning of the fourth day of pregnancy (12, 13). Whether E2 stimulates implantation directly or through secondary factor(s) is currently an area of much interest. One factor essential for embryo implantation is the cytokine leukemia inhibitory factor (LIF) (14). LIF is transiently expressed in the glandular epithelium of mice at ovulation and again on the fourth day of pregnancy (15, 16). In other mammalian species, including the human, LIF expression in the uterus also is up-regulated around the onset of embryo implantation, suggesting that LIF may be of general significance to embryo implantation in mammals (17, 18, 19).
Female mice carrying a null mutation in the LIF gene are sterile because blastocysts do not implant. Reciprocal transfer of blastocysts between wild-type and LIF-deficient females showed that implantation failure was due to a defective maternal uterine environment rather than deficiencies in the embryo (14). The basis for the inability of the uterus to respond to blastocysts has not been established. Here, we show that in LIF-deficient female mice, up to the onset of implantation, uterine cell proliferation, hormone levels, gene expression, and embryo development does not differ from those observed in wild-type females. However, LIF-deficient uteri do not respond to some decidualizing signals. Embryo implantation in LIF deficient females can be rescued by ip injection of recombinant LIF with the embryos developing to term and surviving to adulthood. Implantation and decidualization can also be induced in hormone primed ovariectomized mice by substituting LIF for nidatory E2, revealing that nidatory E2 is only required to induce LIF. Uterine expression of LIF, under the control of nidatory E2, is therefore essential for inducing a fully receptive state to the uterus and is not essential for subsequent embryonic development or for the maintenance of pregnancy.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-methyl-17-hydroxy-progesterone acetate
(Depo-Provera-P4,
Pharmacia, Inc., Peapack, NJ), followed 3 days later by a
single injection of 40 ng of E2. In some
instances the last injection of E2 was omitted or
was substituted by ip injection of LIF or the microinjection of 3 µl
of LIF or PBS into the right uterine horn. To induce decidualization,
the right uterus of the hormone primed or control mice was injected
with 50 µl of paraffin oil. The contralateral horn was used as a
control. When embryos were used for implantation studies, the embryos
were isolated from superovulated mice at the 8-cell stage and cultured
overnight in KSOM (20) medium before their surgical
transfer into the recipient uteri as blastocysts. For cell
proliferation analysis, mice were injected with a single dose of BrdU
of 100 µg/g body weight 15 h after the last injection of
E2. Two hours later, the mice were killed and the
uteri processed for histological and quantitative analysis. Statistical
comparisons were performed using Student’s two tailed t
test or oneway ANOVA to determine whether the treatments were
significant (P < 0.05).
LIF production
Recombinant LIF was produced using pGeX-mLIF and was expressed
as a glutathione S-transferase fusion protein in Escherichia
coli JM109. The expression, purification, and cleavage of fusion
mLIF protein was essentially performed as previously described
(21). Purity was determined by inspection of
silver-stained SDS-PAGE gels run in a Amersham Pharmacia Biotech. Phast gel system and the biological activity of
LIF was determined by the Coomassie Plus Protein Assay and Ba/F3 cell
proliferation assay (22).
Hormone measurement
P4 levels were quantified using by RIA and
performed according to the manufactures instructions (Diagostics Systems Laboratories, Inc., Webster, TX).
Histology
Tissues for routine histological analysis were fixed in 4%
paraformaldehyde, embedded, sectioned at 6 µm and stained using H and
E. Fixation for the BrdU labeled uteri was in 70% ethanol. The tissues
were then processed and stained using an antibody to BrdU according to
the manufacturer’s instructions (DAKO Corp.). Uterine
cells undergoing DNA synthesis were counted within a fixed area and
expressed as the percentage of the total number of cells within the
area. For alkaline phosphatase staining the tissues were fixed and
processed according the established procedures although the tissues
were embedded and sectioned in 55 C melting point wax
(23).
Molecular analysis
Northern analysis and the measurement of LIF mRNA levels by
RNase protection was performed as previously described
(15) and quantified using NIH image quant software. Probes
to Muc-1 and lactoferrin were generated by RT-PCR, cloned into
pGEMTeasy and confirmed by sequencing. The primers for the murine
Mucin-1 (Muc-1) cDNA were: forward, 5'-TCATCTCAGGACACCAGCAGTTC-3';
reverse, 5'-ACTGTGGACTACTGGAGAGCTGTTG-3' and corresponded to the region
in the Muc-1 cDNA between 1358 and 1657 bp. The primers for the murine
Lactoferrin cDNA were: forward, 5'-TTGTGTGAACAGACCAGTGGGAG-3'; reverse,
5'-TTCTGCAAGACAGTGGAGTCCTTC-3' and corresponded to the region between
1360 to 1740 bp in the cDNA.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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day 1). Throughout the remainder of the
cycle and during pregnancy LIF continues to be expressed in the uterus
at basal levels (15, 16). As LIF is highly expressed at
ovulation, it may be required to mediate E2- and
P4-induced changes in uterine cell proliferation
and gene expression before implantation. We compared the distribution
and numbers of uterine cells undergoing proliferation in ovariectomized
wild-type and LIF deficient females following injection with
E2 alone or in combination with
P4. In normal mice, E2
alone induces proliferation in the glandular and luminal epithelium.
When P4 is given 3 days after
E2, it suppresses epithelial proliferation,
induces morphological changes in the epithelium with the cells assuming
a columnar and secretory phenotype and primes the stroma for
proliferation. A second injection of E2, 3 days
later, induces stromal cell proliferation with DNA replication peaking
15 h after E2 injection. A histological and
quantitative comparison of the uteri following BrdU labeling revealed
no statistically significant differences in the distribution and
percentage of cells undergoing DNA synthesis between wild-type and
LIF-deficient uteri following both hormonal regimens. This revealed
that LIF expression was not essential to mediating the effects of
E2 and P4 on uterine cell
proliferation (Fig. 1A
). Similarly, we
compared the expression of two proteins lactoferrin and Muc-1, which
are expressed in the glandular and luminal epithelia and are regulated
by E2 and P4 (24, 25). Both proteins are expressed in the epithelium during
preimplantation development with their levels declining during the
first 3–4 days of pregnancy. Again, we saw no detectable differences
in their levels of expression in the uteri of wild-type and
LIF-deficient mice apart from a weak signal on D5 in the wild-type
uteri that was not seen in the LIF-deficient uteri (Fig. 1B). We also
measured P4 levels over the first 7 days of
pregnancy following mating. Although there was substantial variation
between individuals in the systemic levels of P4,
in both wild-type and LIF-deficient mice, P4
concentrations steadily rose over the first 7 days following mating to
levels previously reported, indicating that loss of LIF had no
significant role in regulating P4 levels (Fig. 1C). From these results, we conclude that LIF expression at ovulation
is not a significant factor in mediating the changes in uterine cell
proliferation, gene expression, and in the increase in
P4 during the first 7 days of pregnancy.
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). Similarly, systemic injection of
pregnant LIF-deficient females, on day 5 with Pontamine Blue revealed
no evidence of localized uterine edema, which is one of the earliest
indications of implantation starting.
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, A–D).
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). We then sought to determine
whether LIF could substitute for nidatory E2.
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and
show that a single injection of 10 µg was sufficient to result in
embryo implantation at rates comparable to those achieved with
E2. Similar rates of implantation were also
attained by giving 4 injections of LIF of 1 µg over an 8-h period.
However, six injections of LIF at 0.5 µg were unsuccessful at
inducing implantation. Injection of the mice with PBS did not result in
implantation and unimplanted blastocysts showing the typical morphology
of those in delay were recovered from the uteri of these females.
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and show
that LIF at a dose as low as 25 ng when injected directly into the
uterine lumen of wild-type mice was able to induce blastocyst
implantation with subsequent normal embryogenesis. Controls, in which
only PBS was injected into the lumen, did not result in blastocyst
implantation and unimplanted blastocysts were recovered following
flushing of the uteri. We also compared the extent to which
decidualization could be induced by either LIF or
E2 following oil injection into the uterine
lumen. Ovariectomized wild-type mice were hormonally primed with
E2 and P4 and then injected
with either 5 µg of LIF or 40 ng of E2 3 days
after P4. Twelve hours later 50 µl of paraffin
oil was injected intraluminally, and the uteri were removed and weighed
48 h later. These results are presented in Fig. 5 and show that LIF injection was equally
effective as E2 at inducing decidualization with
no statistically significant difference between LIF and
E2 in the level to which decidualization was
induced.
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).
Southern analysis on their genotypes confirmed that all the offspring
were homozygous for the mutated LIF allele (data not shown). These
results demonstrated that administration of LIF to pregnant LIF
deficient females restored embryo implantation, with the implanted
embryos developing normally to term.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In rodents, implantation and decidualization are normally initiated by a nidatory surge in E2 levels (12, 13). The transient rise of E2 on the fourth day of pregnancy has pleiotropic effects, inducing a variety of transcription factors, growth factors, and changes in cell proliferation in the uterine stromal cells (28). Some of these factors may be essential to the implantation process. Among these is LIF, in which transcription is up-regulated in the glandular epithelium within 1 h of estrogen administration, with expression persisting for 5–6 h before declining to basal levels. By substituting LIF for nidatory E2 in ovariectomized mice, we showed that it is an essential factor downstream to E2 that probably functions by initiating changes in the uterine epithelium that result in blastocyst implantation and decidualization. Furthermore, ip injection of LIF into pregnant LIF-deficient females was sufficient to rescue embryo implantation failure, resulting in the LIF-deficient females giving birth to viable offspring. This revealed that during the mouse’s life cycle, LIF is essential for initiating implantation but is not required for embryonic development or for the maintenance of pregnancy as has been previously suggested (29). However, it remains unclear what is the role of increased levels of LIF at ovulation. One possibility is that this is a consequence of the high levels of estrogen at ovulation inducing LIF, but the uterus is unresponsive to LIF in the absence of P4.
The ip doses of LIF required to induce implantation were relatively high. This may have been due to the rapid clearance of recombinant LIF from the circulation (t1/2 = 3–5 min) and that injected LIF is accumulated at high levels, by the liver, pancreas, spleen and lungs, preventing access of sufficient biologically active LIF to the uterus (30). This was supported by the observation that much lower doses of LIF when directly injected into the uterine lumen were effective at inducing embryo implantation.
How LIF acts to induce implantation is still not understood. It is possible that it could act on the hypothalamic-pituitary axis where LIF can influence hormone synthesis and therefore may indirectly affect ovarian and/or uterine function (31). However, at present we favor a paracrine mechanism in that the target for LIF’s action in the uterus is the luminal epithelium. The heterodimeric LIF receptor, consisting of the LIFrß and the transmembrane protein gp130, are localized to the glandular and luminal epithelia (17, 32, 33). Neither component is expressed at detectable levels in stromal cells. Secreted LIF has also been detected in uterine washings (34, 35), and we have evidence that intact luminal epithelium isolated from the uterus responds to LIF by the activation of a variety of signal transduction pathways including the phosphorylation and nuclear translocation of STAT transcription factors (33). Blastocysts also express the heterodimeric LIF receptor (32). However, it is unlikely that blastocyst responsiveness to LIF at implantation is essential, as embryos homozygous for loss of either the LIF receptor ß or gp130, both of which are required to form a functional receptor, can implant and undergo postimplantation development (36, 37). Furthermore, direct injection of LIF, at relatively low doses, into the uterine lumen is effective at inducing embryo implantation. Therefore, LIF, secreted from the glandular epithelium in response to a rise in nidatory E2, binds to receptors on the luminal epithelium and so activates signal transduction pathways that result in transcriptional changes in the epithelium. In turn, these result in a change in receptivity of the luminal epithelium allowing the blastocyst that is in apposition, to start to invade the epithelium and underlying stroma. The stroma responds to the invading blastocyst and now responsive epithelium by undergoing localized decidualization at the site of implantation. Once these changes have been initiated, LIF is no longer required by either the mother or the embryo for fetal development to term. Because ovulation, fertilization, and development to the blastocyst stage occur in LIF-deficient females, and implantation is rescued by the injection of LIF, this demonstrates that preimplantation development of the embryo and preparation of the uterus up to blastocyst apposition with the luminal epithelium may also be independent of LIF.
Changes in uterine cell proliferation and gene expression are driven by
the ovarian steroid hormones E2 and
P4. These hormones act either directly on cells
or through locally produced cytokines/growth factors that act in an
autocrine/paracrine manner. The steroidal regulation of many growth
factors and cytokines has been well documented (38, 39).
However, which factors are essential to mediating the changes in
uterine physiology in response to E2 and
P4 is only being established by the use of gene
targeting experiments or the identification of spontaneous (14, 40, 41, 42, 43, 44). As an example, the evidence for the epidermal growth
factor family (EGF) regulating uterine cell proliferation in response
to E2 has been compelling (7, 45, 46, 47, 48). It is nevertheless evident that there is substantial
redundancy within this family of growth factors regarding their roles
in regulating cell proliferation and other changes in the uterus, as
mice simultaneously deficient for three of the factors (EGF, TGF-
and amphiregulin) are fertile (49).
In conclusion, transient expression of LIF in the uterus, induced by the nidatory rise in E2 levels, at the time of embryo implantation, is essential to inducing a state of receptivity in the uterine epithelium, allowing both blastocyst invasion and stromal decidualization. LIF is neither required for both pre- and postimplantation embryogenesis nor for the maintenance of pregnancy. Current investigations are focused on determining what factors are regulated in the luminal epithelium by the action of LIF on this tissue. Identification of these factors should provide deeper insights into how this complex, but vital process of implantation is regulated.
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Acknowledgments |
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Footnotes |
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2 Present address: Department of Pathology, Chang Gung Memorial
Hospital Linkou, Kwei San, Tao Yuan, Taiwan.
Received June 30, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is a potential mediator of estrogen action in the mouse
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H.-F. Chen, C.-Y. Lin, K.-H. Chao, M.-Y. Wu, Y.-S. Yang, and H.-N. Ho Defective Production of Interleukin-11 by Decidua and Chorionic Villi in Human Anembryonic Pregnancy J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2320 - 2328. [Abstract] [Full Text] [PDF]
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J.-G. Cheng, J. R. Chen, L. Hernandez, W. G. Alvord, and C. L. Stewart Dual control of LIF expression and LIF receptor function regulate Stat3 activation at the onset of uterine receptivity and embryo implantation PNAS, June 28, 2001; (2001) 151180898. [Abstract] [Full Text] [PDF]
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J.-G. Cheng, J. R. Chen, L. Hernandez, W. G. Alvord, and C. L. Stewart Dual control of LIF expression and LIF receptor function regulate Stat3 activation at the onset of uterine receptivity and embryo implantation PNAS, July 17, 2001; 98(15): 8680 - 8685. [Abstract] [Full Text] [PDF]
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