Abstract
IntroductionThe 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).MethodsHere 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).ResultsWe 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.ConclusionsOur 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.
Highlights
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
In this study we tested whether the trophoblastic hormones human chorionic gonadotropin (hCG) and P4 signal human embryonic stem cells (hESCs) proliferation and differentiation. By using this in vitro model of early human embryogenesis, we found that hCG/luteinizing hormone (LH) signal via LH/ human chorionic gonadotropin receptor (LHCGR) to promote hESC proliferation and steroidogenesis (P4 synthesis), and that P4 signaling is obligatory for both embryoid bodies (EBs) and neuroectodermal rosette differentiation
To examine the functionality of trophoblastic hCG signaling to the embryoblast, we first examined whether the LHCGR was expressed by pluripotent hESCs
Summary
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. 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). 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. It is known that (hyperglycosylated) hCGb has potent cell growth and invasion properties and acts as an autocrine factor on extravillous invasive cytotrophoblast cells to initiate and control invasion during implantation and the establishment of hemochorial placentation [12]. hCG promotes these processes during malignancy in invasive hydatidiform mole, choriocarcinoma, and testicular cancers [12]
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