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


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Gallego
Miguel J
MJ
Geriatric Research, Education and Clinical Center, Veterans Administration Hospital and Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, 2500 Highland Avenue, Madison, WI 53705, USA. csa@medicine.wisc.edu
Porayette
Prashob
P
Kaltcheva
Maria M
MM
Bowen
Richard L
RL
Vadakkadath Meethal
Sivan
S
Atwood
Craig S
CS
D001692:Biological Transport; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D006063:Chorionic Gonadotropin / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology; D064231:Nestin / Q000096:biosynthesis; D054258:Neural Plate / Q000166:cytology; D054261:Neurulation / Q000502:physiology*; D010750:Phosphoproteins / Q000096:biosynthesis / Q000378:metabolism; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism*; D011974:Receptors, LH / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism; D012397:Rosette Formation; D015398:Signal Transduction / Q000187:drug effects; D000098682:Steroidogenic Acute Regulatory Protein
D006063:Chorionic Gonadotropin; D006727:Hormone Antagonists; D064231:Nestin; D010750:Phosphoproteins; D011974:Receptors, LH; D011980:Receptors, Progesterone; C101118:progesterone receptor A; D000098682:Steroidogenic Acute Regulatory Protein; D015735:Mifepristone; D011374:Progesterone; D002784:Cholesterol