The pregnancy hormones human chorionic gonadotropin and progesterone induce human embryonic stem cell proliferation and differentiation into neuroectodermal rosettes

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.

Human chorionic gonadotropin from day 2 spent embryo culture media and its relationship to embryo development

“…Although the hCG molecule was the first marker produced by an embryo identified in the spent embryo culture media (3), no further attempts to establish its use as a potential marker of embryo competence has been reported to our knowledge. Its specific function at this stage of embryonic development is currently not known (3,22,23). However, recent studies have suggested that the hCG molecule may be involved in the growth and development of the embryoblast at the early stages and implantation at the later stages of development (23).…”

Effect of pregnancy on the proliferation of rat adipose-derived stem cells

“…For example, several studies have reported that hormones affect the proliferation and differentiation capacities of human or mouse MSCs (Kuo et al, 2013;Yazawa et al, 2014). Since the levels of sex hormones fluctuate during a woman's life, proliferation and differentiation of ADSCs might also be affected (Gallego et al, 2010;Hirschberg, 2012;Rossi et al, 2014). However, there are no evidence-based studies till date on this subject.…”

BAG2 Is Repressed by NF-κB Signaling, and Its Overexpression Is Sufficient to Shift Aβ1-42 from Neurotrophic to Neurotoxic in Undifferentiated SH-SY5Y Neuroblastoma

“…Progesterone, an endogenous and physiologically regulated inhibitor of NF-κB signaling, has been shown to be an important modulator of NF-κB activity following traumatic brain injury, during infection and throughout the menstrual cycle (Brenner et al 2002;Chen et al 2008;Lei et al 2014). Further, progesterone signaling has been found to be essential for embryoid body formation and neurectodermal specification (Gallego et al 2009(Gallego et al , 2010. These crucial progesterone-dependent cell fate decisions also coincide with an increase in BAG2 expression (Barrett et al 2005) suggesting that developmentally regulated NF-κB by progesterone signaling may cause a downstream derepression of NF-κB target genes.…”