The capability of cytotrophoblast cells to produce hCG, progesterone, estrogen, cGnRH and beta-endorphin in vitro has been demonstrated in serum-free culture medium. Before experiment, a 24-h preculture was carried out in order to remove the endogenous hormones of the tissue. During a period of 8 days' culture, the cytotrophoblast cells could constantly produce a small amount of hCG. The production of progesterone rose rapidly and became doubled within six days. The estrogen secretion showed a similar pattern in the presence of androstenedione, a precursor of estrogen, indicating the elevation of aromatase activity in the cells. The elevation of the enzyme activity has been further demonstrated not to be induced by androstenedione. In both cytotrophoblast and syncytiotrophoblast cell cultures, cGnRH was only detected in the culture of cytotrophoblast cells, with a value up to 4 pg/10(5) cells/24 h. However, beta-endorphin was identified both in cytotrophoblast and syncytiotrophoblast cells. Its content increased significantly in the medium of cytotrophoblast cell culture from the 4th to 6th days, but declined in the medium of syncytiotrophoblast cell culture. The results demonstrate clearly that the cytotrophoblast cells are the sole origin of GnRH in human placenta and are also able to synthesize beta-endorphin and steroid hormones. The findings indicate that there is no such a sharp functional demarcation existing between these two kinds of trophoblast cells as suggested before. The data are of significance for a better understanding of the mechanism of hormonal regulation in placenta.
"Trophoblastic production of endorphins (Zhuang and Li 1991) also is crucial for embryogenesis (Gallego et al. 2009). Treatment of hESC colonies with the delta opioid receptor selective antagonist ICI 174,864 (Corbett et al. 1984; Paterson et al. 1984) inhibits the formation of the EB cystic structure, and instead forms non-spherical structures ~40% the size of normal spheroidal EBs. "
"Zygotic division into a blastocyst establishes the extraembryonic tissues (trophoblast layer or outer cell mass) that support the embryonic embryoblast (inner cell mass) early in embryogenesis. Trophoblasts secrete an array of hormones [1-4], including hCG, during the migration of the blastocyst through the fallopian tube and its implantation into the endometrium. The dramatic elevation in the production of hCG by trophoblasts at this early embryonic stage (from 5 to ≥1,000 mIU/ml in the maternal serum) [2,5] signals both the corpus luteum and trophoblast  to synthesize and secrete P4 . "
[Show abstract][Hide abstract] ABSTRACT: The physiological signals that direct the division and differentiation of the zygote to form a blastocyst, and subsequent embryonic stem cell division and differentiation during early embryogenesis, are unknown. Although a number of growth factors, including the pregnancy-associated hormone human chorionic gonadotropin (hCG) are secreted by trophoblasts that lie adjacent to the embryoblast in the blastocyst, it is not known whether these growth factors directly signal human embryonic stem cells (hESCs).
Here we used hESCs as a model of inner cell mass differentiation to examine the hormonal requirements for the formation of embryoid bodies (EB's; akin to blastulation) and neuroectodermal rosettes (akin to neurulation).
We found that hCG promotes the division of hESCs and their differentiation into EB's and neuroectodermal rosettes. Inhibition of luteinizing hormone/chorionic gonadotropin receptor (LHCGR) signaling suppresses hESC proliferation, an effect that is reversed by treatment with hCG. hCG treatment rapidly upregulates steroidogenic acute regulatory protein (StAR)-mediated cholesterol transport and the synthesis of progesterone (P4). hESCs express P4 receptor A, and treatment of hESC colonies with P4 induces neurulation, as demonstrated by the expression of nestin and the formation of columnar neuroectodermal cells that organize into neural tubelike rosettes. Suppression of P4 signaling by withdrawing P4 or treating with the P4-receptor antagonist RU-486 inhibits the differentiation of hESC colonies into EB's and rosettes.
Our findings indicate that hCG signaling via LHCGR on hESC promotes proliferation and differentiation during blastulation and neurulation. These findings suggest that trophoblastic hCG secretion and signaling to the adjacent embryoblast could be the commencement of trophic support by placental tissues in the growth and development of the human embryo.
[Show abstract][Hide abstract] ABSTRACT: Division of the human zygote leads to the formation of the blastocyst that contains human embryonic stem cells (hESC) which develop into the embryo. Little is known about the physiological signals that direct hESC division and differentiation during early embryogenesis. A number of growth factors, including the pregnancy-associated hormone human chorionic gonadotropin (hCG), are secreted by trophoblasts^1-3^ that lie adjacent to the embryoblast in the blastocyst, but it is not known whether these growth factors directly signal the epiblast. Here we show that hCG promotes the division of embryoblast-derived inner mass cells (hESC), and their differentiation during blastulation and neurulation. Inhibition of LH/hCG receptor (LHCGR) signaling with P-antisense oligonucleotides suppresses hESC proliferation. Similarly, hESC proliferation can be blocked using an antibody against the extracellular activation site of LHCGR, an effect that is reversed by treatment with hCG. hCG treatment rapidly upregulates steroidogenic acute regulatory protein-mediated cholesterol transport and the synthesis of progesterone, a neurogenic steroid^4,5^. Treatment of hESC colonies with progesterone induces neurulation as demonstrated by the expression of nestin and the formation of columnar neuroectodermal cells that organize into neural tube-like rosettes. Suppression of progesterone signaling by withdrawing progesterone or treating with the progesterone receptor antagonist RU-486 inhibits the differentiation of hESC colonies into embryoid bodies (blastulation) and rosettes (neurulation). These results explain the default pathway of hESC differentiation towards a neural stem cell fate in vitro. Collectively, our findings implicate trophoblastic hCG secretion and signaling via LHCGR on the adjacent embryoblast in the induction of hESC proliferation and differentiation into blastocysts and neurula. This paracrine/juxtacrine signaling by extraembryonic tissues is the commencement of trophic support by placental tissues in the growth and development of the human embryo.
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