The Human placenta: an atypical endocrine organ

La placenta humana es caracteritza per la intensitat i especificitat de les seves funcions endocrines. La hormones de la placenta són necessàries per a l'establiment i manteniment de l'embaràs, per a l'adaptació a aquest de l'organisme femení, per al creixement del fetus així i per al desenvolupament dels mecanismes implicats en el part. El teixit endocrí de la placenta és el sinciciotrofoblast, que cobreix les vellositats coriòniques o estructura principal d'intercanvi. La utilització de cultius primaris de citotrofoblasts ha proporcionat molta informació sobre els mecanismes implicats en la formació del sinciciotrofoblast per fusió cèll. ula-cèll. ula. Immers en la sang materna, el sinciciotrofoblast secreta la major part de les seves hormones polipeptídiques a la circulació materna. Entre d'altres, la gonadotrofina coriònica (hCG) fa una funció essencial en el manteniment del cos luti i està directament implicada en la diferenciació del trofoblast. L'hormona de creixement (GH) placentària està també secretada contínuament pel sinciciotrofoblast i substitueix la GH hipofisària durant l'embaràs. Mitjançant la captura del colesterol a partir de les lipoproteïnes maternes, el sinciciotrofoblast sintetitza una gran quantitat de progesterona necessària per a l'estabilitat de l'úter. El sinciciotrofoblast, en no tenir l'enzim citocrom P450 17 α-hidroxilasa/17-20-liasa, utilitza els andrògens adrenals materns i fetals per a sintetizar estrògens. Com a conclusió, és important esmentar que en l'observació de qualsevol anomalia hormonal durant l'embaràs hauràn de tenir-se en compte aquestes dades i, en particular, les característiques enzimàtiques de la placenta.The human placenta is characterized by the intensity and the specificity of its endocrine functions. Placental hormones are required for the establishment and maintenance of pregnancy, the adaptation of the maternal organism to pregnancy, fetal growth and well being, and the development of the mechanisms involved in parturition. The endocrine tissue of the placenta is the syncytiotrophoblast, which covers the chorionic villi, the main structure of exchange. Primary cultures of villous cytotrophoblasts have provided insight into the mechanisms involved in syncytiotrophoblast formation by cell-cell fusion. Bathing in maternal blood, the syncytiotrophoblast secretes the majority of its polypeptide hormones into maternal circulation. Among those, hCG (human chorionic gonadotropin) plays an essential role in the maintenance of the corpus luteum and is directly implicated in trophoblastic differentiation. The placental GH (growth hormone) secreted continuously by the syncytiotrophoblast replaces the maternal pituitary GH during pregnancy. Capturing the cholesterol from the maternal lipoproteins, the syncytiotrophoblast synthesizes large amounts of progesterone essential for uterine quiescence. Deprived of cytochrome P450 17αhydroxylase/17-20lyase, it uses the maternal and fetal adrenal androgens to synthesize estrogens. The observation of any maternal hormonal anomaly during pregnancy must take into account these data and, in particular, the enzymatic characteristics of the placenta

Rapid Effect of Treatment of Psoriatic Erythrocytes with the Synthetic Retinoid Acitretin to Increase 8-Azido Cyclic AMP Bindings to the RI Regulatory Subunit

We have recently demonstrated a deficiency in the cyclic adenosine monophosphate (cAMP) – dependent protein kinases (PKA), the intracellular mediator of AMP, in psoriasis. This enzyme defect is expressed in fibroblasts and in red blood cells isolated from psoriatic patients. In these cells, the abnormality noted in cAMP binding to PKA correlates well with the severity of the disease and is corrected by long-term treatment with etretinate. In this study, we determined the effect of oral administration of acitretin in four psoriatic patients on the altered cAMP binding observed with the RI regulatory subunit of PKA in erythrocytes prepared from these patients. Acitretin (30 mg/day) induced a rapid (within 1 h) increase in the ability of the RI regulatory subunit of erythrocytes to bind the 8-azido[32P]cAMP photoaffinity analogue of cAMP. The maximal plateau for this effect of acitretin was observed within 24 h of treatment and preceded the clinical improvement of the disease. The effect of acitretin was dose-dependent, with the maximal response observed at 40 mg acitretin/d. In addition, the rapid exposure (15 mm) of erythrocytes isolated from untreated patients exhibiting severe psoriasis to acitretin also promoted an increase in binding of 8-azido[32P]cAMP to the RI cAMP binding protein. Retinoic acid and 13-cis-retinoic acid were as efficient as acitretin in inducing the increase in binding of 8- azido[32P]cAMP to the RI regulatory subunit, whereas arotinoid was without effect. These results suggest that acitretin may act to modify PKA (the RI regulatory subunit) at the post-transcriptional level, and this may reflect, in part, on the mechanism of action of this synthetic retinoid. Further, monitoring this biochemical event may be helpful in determining the choice of retinoid therapy and in the management of its pharmacology

Biochemical characterization and modulation of LH/CG-receptor during human trophoblast differentiation.: LH/CG-R in human trophoblast differentiation.

Due to the key role of the human chorionic gonadotropin hormone (hCG) in placental development, the aim of this study was to characterize the human trophoblastic luteinizing hormone/chorionic gonadotropin receptor (LH/CG-R) and to investigate its expression using the in vitro model of human cytotrophoblast differentiation into syncytiotrophoblast. We confirmed by in situ immunochemistry and in cultured cells, that LH/CG-R is expressed in both villous cytotrophoblasts and syncytiotrophoblasts. However, LH/CG-R expression decreased during trophoblast fusion and differentiation, while the expression of hCG and hPL (specific markers of syncytiotrophoblast formation) increased. A decrease in LH/CG-R mRNA during trophoblast differentiation was observed by means of semi-quantitative RT-PCR with two sets of primers. A corresponding decrease ( approximately 60%) in LH/CG-R protein content was shown by Western-blot and immunoprecipitation experiments. The amount of the mature form of LH/CG-R, detected as a 90-kDa band specifically binding (125)I-hCG, was lower in syncytiotrophoblasts than in cytotrophoblasts. This was confirmed by Scatchard analysis of binding data on cultured cells. Maximum binding at the cell surface decreased from 3,511 to about 929 molecules/seeded cells with a kDa of 0.4-0.5 nM. Moreover, on stimulation by recombinant hCG, the syncytiotrophoblast produced less cyclic AMP than cytotrophoblasts, indicating that LH/CG-R expression is regulated during human villous trophoblast differentiation. J. Cell. Physiol. 212: 26-35, 2007. (c) 2007 Wiley-Liss, Inc

Overexpression of copper zinc superoxide dismutase impairs human trophoblast cell fusion and differentiation.: SOD-1 and Human Trophoblast Differentiation

The syncytiotrophoblast is the major component of the human placenta, involved in feto-maternal exchanges and secretion of pregnancy-specific hormones. Multinucleated syncytiotrophoblast arises from fusion of mononuclear cytotrophoblast cells. In trisomy 21-affected placentas, we recently have shown that there is a defect in syncytiotrophoblast formation and a decrease in the production of pregnancy-specific hormones. Due to the role of oxygen free radicals in trophoblast cell differentiation, we investigated the role of the key antioxidant enzyme, copper/zinc superoxide dismutase, encoded by chromosome 21 in in vitro trophoblast differentiation. We first observed that overexpression of superoxide dismutase in normal cytotrophoblasts impaired syncytiotrophoblast formation. This was associated with a significant decrease in mRNA transcript levels and secretion of hCG and other hormonal markers of syncytiotrophoblast. We confirmed abnormal cell fusion by overexpression of green fluorescence protein-tagged superoxide dismutase in cytotrophoblasts. In addition, a significant decrease in syncytin transcript levels was observed in superoxide dismutase-transfected cells. We then examined superoxide dismutase expression and activity in isolated trophoblast cells from trisomy 21-affected placentas. Superoxide dismutase mRNA expression (P < 0.05), protein levels (P < 0.01), and activity (P < 0.05) were significantly higher in trophoblast cells isolated from trisomy 21-affected placentas than in those from normal placentas. These results suggest that superoxide dismutase overexpression may directly impair trophoblast cell differentiation and fusion, and superoxide dismutase overexpression in Down's syndrome may be responsible at least in part for the failure of syncytiotrophoblast formation observed in trisomy 21-affected placentas

Effects of Phosphodiesterase 4 Inhibition on Alveolarization and Hyperoxia Toxicity in Newborn Rats

International audienceBACKGROUND: Prolonged neonatal exposure to hyperoxia is associated with high mortality, leukocyte influx in airspaces, and impaired alveolarization. Inhibitors of type 4 phosphodiesterases are potent anti-inflammatory drugs now proposed for lung disorders. The current study was undertaken to determine the effects of the prototypal phosphodiesterase-4 inhibitor rolipram on alveolar development and on hyperoxia-induced lung injury. METHODOLOGY/FINDINGS: Rat pups were placed under hyperoxia (FiO2>95%) or room air from birth, and received rolipram or its diluent daily until sacrifice. Mortality rate, weight gain and parameters of lung morphometry were recorded on day 10. Differential cell count and cytokine levels in bronchoalveolar lavage and cytokine mRNA levels in whole lung were recorded on day 6. Rolipram diminished weight gain either under air or hyperoxia. Hyperoxia induced huge mortality rate reaching 70% at day 10, which was prevented by rolipram. Leukocyte influx in bronchoalveolar lavage under hyperoxia was significantly diminished by rolipram. Hyperoxia increased transcript and protein levels of IL-6, MCP1, and osteopontin; rolipram inhibited the increase of these proteins. Alveolarization was impaired by hyperoxia and was not restored by rolipram. Under room air, rolipram-treated pups had significant decrease of Radial Alveolar Count. CONCLUSIONS: Although inhibition of phosphodiesterases 4 prevented mortality and lung inflammation induced by hyperoxia, it had no effect on alveolarization impairment, which might be accounted for by the aggressiveness of the model. The less complex structure of immature lungs of rolipram-treated pups as compared with diluent-treated pups under room air may be explained by the profound effect of PDE4 inhibition on weight gain that interfered with normal alveolarization

Facteurs de croissance et développement embryonnaire

International audienc

Tumorigénèse hypophysaire (vers l'identification de marqueurs d'invasion tumorale et/ou de facteurs prédictifs de récidive des adénomes hypophysaires)

Les adénomes hypophysaires sont des tumeurs bénignes qui peuvent devenir localement invasives dans 40% des cas et/ou récidiver dans un délai variable après la chirurgie. L'absence de marqueur d'invasion tumorale et/ou de récidive pose des problèmes en pratique clinique, notamment pour poser l'indication d'une radiothérapie complémentaire de la chirurgie. Grâce à une approche transcriptomique comparative d'un groupe d'adénomes cliniquement non fonctionnels (ACNFs) invasifs (n = 22) par rapport à un groupe d'ACNFs non invasifs (n = 18), nous mettons en évidence l'expression différentielle de 346 gènes entre les deux sous-groupes et le confirmons en PCR quantitative pour quatre gènes (p < 0,05) : IGFBP5, MYO5A, FLT3 etNFE2Ll. Seul le produit d'un de ces gènes, MYO5A, est plus exprimé dans les adénomes hypophysaires invasifs en immunohistochimie. Ce marqueur est bien corrélé à la l'expression de la protéine PTTG. Les immunomarquages pour Ki67, MMP9, p53 ne sont pas différents entre les deux groupes.Pituitary adenomas are considered as benign tumors but approximately 40% of them are locally invasive and/or relapse may occur after surgical removal in a significant proportion of patients. Markers of invasiveness or predictive factors of relapse are needed to guide patient management, and particularly the use of adjuvant therapy On the basis of a comparative transcriptomic analysis between a group of 22 invasive non functioning pituitary adenomas (NFPAs) and a group of 18 non invasive NFPAs, we show that the expression of 346 genes differed between invasive and non invasive NFPAs (p<0,001). Among the 35 genes selected for quantification by qRT-PCR, overexpression of only four genes was confirmed (p < 0,05) namely IGFBP5, MYO5A, FLT3 et NFE2L1. At the protein level, only myosin 5 A immunostaining was stronger in invasive than in non invasive NFPAs and correlated positively with PTTG immunostaining. Immunostaining of other markers including Ki67, p53 and MMP9 showed no difference between the two groups.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Etude de la vascularisation utéro-placentaire humaine (rôle du trophoblaste dans le remodelage vasculaire utérin et la physiopathologie de la préeclampsie)

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF