Auswahl der wissenschaftlichen Literatur zum Thema „Régulations endocrine et paracrine“

Endothelin (ET) contributes to the increased systemic vascular resistance and elevated cardiac filling pressures seen in congestive heart failure (CHF). We investigated to what extent ET-mediated vasoconstriction in CHF occurs through an endocrine action of elevated plasma ET or by an autocrine/paracrine mechanism related to induction of vascular ET gene expression. Three weeks of pacing (225 beats/min) induced a marked release of ET-1 from the pulmonary circulation with a sixfold elevation of arterial plasma ET in CHF pigs compared with sham-operated pigs. Arterial plasma ET was the strongest and only independent predictor of systemic vascular resistance. In contrast, vascular preproET-1 and ET-receptor mRNA expression were unaltered or decreased in CHF pigs and did not correlate with indexes of vascular tone. However, myocardial preproET-1 mRNA expression increased twofold in CHF pigs. PreproET-2 and preproET-3 mRNAs were not detectable in cardiovascular tissues. In conclusion, plasma ET was markedly increased because of an augmented release from the pulmonary circulation during CHF, and arterial plasma ET correlated with systemic vascular resistance. The absence of ET induction in the peripheral vasculature suggests that ET increases vascular tone during CHF by an endocrine, not an autocrine/paracrine, mechanism.

Abstract BMP2 and BMP4 play crucial inductive roles during development. In this issue of Blood, Shao et al demonstrate that an intricate network of paracrine BMP2/4 signals also regulates angiogenesis—and will very likely interact with endocrine BMP cues during wound repair.1

The endothelium is the production site of several potent vasoactive substances that modulate vascular tone and growth. The present study was undertaken to investigate the presence and secretion of atrial natriuretic peptide (ANP) immunoreactivity from vascular endothelial cells. ANP immunoreactivity was present in cultured human aortic endothelial cells by both immunohistochemical staining and radioimmunoassay. ANP immunoreactivity was also detectable in culture medium from human aortic endothelial cells in low picogram concentrations. These findings suggest that vascular endothelium is a site of ANP production and secretion of ANP. There was a differential distribution of ANP and endothelin-1 (ET-1), with a higher ANP concentration in cell extracts and a higher ET-1 concentration in cell culture media. Although ANP has been conceived as a circulating endocrine hormone, these findings are consistent with ANP functioning also as an autocrine and paracrine modulator in the regulation of vascular tone and growth.

Abstract The pituitary gland is the master regulator of the endocrine system, housing six major hormone producing cell types. This gland is derived from Rathke’s Pouch, an invagination of the oral ectoderm. Hormone-producing pituitary cell lineages are derived from a population of embryonic cells expressing SOX2. ZFP36L1/Butyrate Response Factor 1 (BRF1) is an RNA binding protein that binds and targets mRNAs of various cytokines and chemokines for degradation prior to translation, attenuating secretion of inflammatory factors (Herranz et al. 2015). Here, we show that BRF1 is a novel marker expressed in SOX2+ cells in human and mouse pituitaries, suggesting that these cells may have a secretory profile. To investigate this possibility, we have combined molecular and genetic studies in vivo. We have used a novel mouse model, R26lsl-mBRF1 that allows the expression of a mutant, constitutively active BRF1 protein upon Cre-mediated recombination, alongside our lab’s models (Hesx1Cre/+ and Sox2CreERT2/+), to express mutant BRF1 in HESX1+ and SOX2+ cells during development and postnatally. This approach results in pituitary hypoplasia and severe hypopituitarism due to a failure of cell-lineage specified cells to differentiate into hormone-producing cells. Hormone production in these mutant cells, however, can be rescued in vitro through co-culture with WT pituitaries and in vivo in chimeric pituitaries, highlighting a cell non-autonomous mechanism underlying the phenotype. Single cell RNA sequencing of WT and Sox2CreERT2/+;R26lsl-mBRF1 murine embryonic pituitaries, as well as use publicly available human pituitary single cell datasets, have allowed us to identify specific cytokines and chemokines secreted by SOX2+ cells, as well as downstream intracellular signalling pathways in differentiating cells (Zhang et al. 2020), which may be responsible for controlling terminal differentiation of hormone-producing cells within the developing pituitary. Together with our recently published data, these results support the notion that SOX2+ pituitary stem cells play a critical paracrine role in controlling progenitor cell proliferation and terminal differentiation (Russell et al. 2021). References: Herranz, Nicolás et al. 2015. “MTOR Regulates MAPKAPK2 Translation to Control the Senescence-Associated Secretory Phenotype.” Nature Cell Biology 17(9): 1205–17. http://www.nature.com/doifinder/10.1038/ncb3225. Russell, John P et al. 2021. “Pituitary Stem Cells Produce Paracrine WNT Signals to Control the Expansion of Their Descendant Progenitor Cells.” eLife. Zhang, Shu et al. 2020. “Single-Cell Transcriptomics Identifies Divergent Developmental Lineage Trajectories during Human Pituitary Development.” Nature Communications.

Background: Portal vein is the most enigmatic vessel of our body because it regulates own contractile performances using a special pace-maker mechanism represented by cells of Cajal. The contribution of various metabolic mediators and natural vasotropic agents in the control of the portal blood circuit is much less studied compared to the arterial system in general and the hepatic system in particular. The studies designed on the structure, function, and reactivity of the portal vein in different preconditioning have brought some common but also distinct evidence of the arterial system. Nitric oxide production is higher partly due to reduced arginase expression, but muscular media is thinner. Periodic spontaneous contractions directed towards the liver gate are characteristic for portal vein (PV), and the longitudinal muscle fibers are considered to be responsible for this phenomenon. Spontaneous rhythmic oscillations of the cells of Cajal are triggered by increasing calcium ion concentration leading to their depolarization. PV constrictor effect of phenylephrine is dependent on the activity of receptors to ET-1. For PV is characterized the acetylcholine induced contraction either in vivo or in vitro, and this effect is thought to be dependent on ET-1. Conclusions: The establishment of main particularities of portal vein reactivity of action of different paracrine, endocrine, and hemodynamical stimuli represents an important tool for prediction of contractile disorders leading plausible to portal hypertension. Likewise, a well proven interplay between cholinergic and adrenergic stimulations and on the other hand between Ang II and ET-1 actions must be a support for pharmacological modulating of portal vein reactivity disorders.

Abstract Growth hormone (GH) is an endocrine and paracrine/autocrine regulator of the hen ovarian function, with the GH receptor concentration in the granulosa layer (GL) being maximum in the largest preovulatory follicle (Lebedeva et al. 2004, Biol.Reprod. 71:1174–1181). In the present study, GH effects on in vitro production of progesterone by GL from the two largest yellow follicles (F1 and F2) were investigated due to the hen age and the presence of the theca layer (TL). Young hens with long clutch (YLC, 32–33 week-old, >10 eggs per clutch) and old hens with short clutch (OSC, 74–76 week-old, 3–6 eggs per clutch) were used. After isolation, GL from F1 and F2 follicles (n = 8–9) was cultured separately or jointly with the respective TL for 18 h in the presence or absence of chicken GH (25 ng/ml). Concentrations of progesterone in culture media were measured by ELISA. The data were analyzed by repeated measures ANOVA. When GL from F1 follicle cultured alone, GH did not affect progesterone production in YLC hens and decreased it from 30,5±3,4 to 20,5±2,9 ng/mg tissue (P < 0.01) in OSC hens. Conversely, when tested GL from F2 follicle, GH increased progesterone output from 15,8±2,4 to 20,4±2,5 ng/mg tissue (P < 0.05) in YLC birds and had no effect on the output in OSC birds. During co-culture of GL and TL, GH raised 1.4–1.5 times the production of progesterone in the case of F1 follicle and did not change it in the case of F2 follicle in hens of both ages. The findings indicate that the steroidogenic response of GL from the two largest preovulatory follicles to GH differs in young and old hens. However, the interaction with TL modifies the GL response and makes it similar in birds regardless the age and reproductive status. The study was supported by RFBR (19-016-00216).

Abstract Cell-mediated (ex-vivo) gene therapy for the treatment of adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) had started in 1990 and nowadays it is the first marketing approval of an ex vivo gene therapy in Europe. The method based on ex-vivo transduction of peripheral blood lymphocytes with retroviral vector carrying the functional ADA gene in 2002 have been improved to use hematopoietic stem cell (HSC) for ex-vivo transduction with 100% survival and the evidence of safety and efficacy. Remarkably, umbilical cord blood mononuclear cells (UCB-MC) were successfully used for treatment of ADA deficiency in neonates as well. Meanwhile SCID is a very rare congenital disorder of the immune system although the option to use peripheral blood lymphocytes as cell carriers of the therapeutic genes for regenerative medicine is highly attractive. In our studies to overcome the neural cells death and stimulate neuroregeneration at neurodegenerative diseases (ALS), spinal cord injury (SCI), and stroke in animal models we employed ex-vivo triple gene therapy based on human UCB-MC transduced with adenoviral vectors carrying vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF) and neural cell adhesion molecule (NCAM). The reason for clinical application of UCB-MC is based on their availability, ease of preparation and potential for long term storage, as well as legislative, ethical and religious benefits for the transplantation. In our gene-cell construct NCAM was used for homing and survival of UCB-MC at the site of neurodegeneration. VEGF and GDNF are the molecules with well-known neuroprotective function. Moreover VEGF is useful in restoring of the microcirculation as well. The positive results in treatment of ALS mice (Islamov et al, 2016), SCI (Izmailov et al, 2017) and stroke in rats (Sokolov et al, 2018) let us to propose the rationality to use of UCB-MC as cell carriers for the therapeutic genes based on:(1) suitability for both auto- and allotransplantation; (2) low immunogenicity; (3) high level of transduction; (4) high capability of synthetic and secretory activity for production of recombinant therapeutic molecules as well as endogenous growth and neurotrophic factors, cytokines and chemokines; (5) the action of therapeutic molecules on target cells via the paracrine or endocrine mechanism; (6) duration of recombinant molecule production limited by adenoviral vector half-life; (7) elimination of UCB-MC in 1-2 month after administration and possible multiple transplantation. Important, cell-mediated gene delivery makes the viral antigens inside the ex-vivo transduced UCB-MC invisible to the recipient immune system and it is easy to control production of recombinant molecules via the level of cell transduction or the number of transplanted cells. Thus, the cord blood mononuclear cells can serve as powerful tools for address delivery of recombinant genes encoding therapeutic molecules for regenerative medicine. This study was supported by the grant of Russian Science Foundation No 16-15-00010. Kazan Federal University was supported by the Russian Government Program of Competitive Growth. Disclosures No relevant conflicts of interest to declare.

La spermatogenèse est un processus hautement spécialisé de prolifération et de différenciation cellulaire conduisant à la production de spermatozoïdes haploïdes à partir de cellules souches spermatogoniales diploïdes. Chez les Gnathostomes, les fonctions testiculaires sont principalement contrôlées de façon endocrine par l’axe hypothalamo-hypophyso-gonadique (HHG) impliquant notamment les GnRHs hypothalamiques et les hormones gonadotropes, FSH et LH, dont l’émergence s’est produite à la racine des Vertébrés cartilagineux. De plus, des fonctions paracrines des GnRHs et de la thyrostimuline ont été explorées au niveau gonadique chez des Vertébrés osseux. L’objet de cette thèse était de caractériser les régulations endocrines et paracrines de la spermatogenèse médiées par les GnRHs et les hormones gonadotropes chez un modèle Élasmobranche, la roussette Scyliorhinus canicula. Ce travail a été étendu à la caractérisation de GPA2 et GPB5, constituant la thyrostimuline, qui correspondent aux orthologues des ancêtres moléculaires des sous-unités des hormones glycoprotéiques. Dans ce travail, l’évolution du protéome testiculaire au cours de la spermatogenèse de S. canicula a été décrite, les neuropeptides GnRHs, les hormones glycoprotéiques FSH, LH, TSH, GPA2 et GPB5, et leurs récepteurs associés ont fait l’objet d’analyses in silico et d’expressions dans différents tissus avec un focus au cours de la spermatogenèse. Il a été observé une expression à tous les stades de la spermatogenèse de fshr, lhr et des récepteurs aux GnRHs au niveau germinale et sertolien, de tshr et gpb5 au niveau sertolien et de gpa2 au niveau germinal, avec des abondances plus importantes associées aux stades spermatides. Ce travail a été complété par des tests fonctionnels in vitro qui ont montré que FSHR pouvait être activé par FSH et LH, LHR uniquement par LH, et que GPB5-GPA2 pouvait activer les trois récepteurs FSHR, LHR et TSHR, suggérant ainsi un rôle paracrine de la thyrostimuline au niveau testiculaire. L’ensemble de ce travail permet de proposer un modèle de régulation de la spermatogenèse chez les Élasmobranches qui associe des hormones endocrines, avec les GnRHs et gonadotropines circulantes, et des hormones paracrines, avec GPA2, GPB5 et les stéroïdes. Ce modèle apparaît cohérent et intermédiaire dans l’évolution des systèmes régulateurs de la spermatogenèse qui seraient passés d’une régulation paracrine prépondérante chez les Bilatériens non-Vertébrés à une régulation endocrine prépondérante chez les Vertébrés osseux avec la mise en place de l’axe hypothalamo-hypophyso-gonadique
Spermatogenesis is a highly specialized process of cell proliferation and differentiation leading to the production of haploid spermatozoa from diploid spermatogonial stem cells. In Gnathostomes, testicular functions are mainly controlled by the endocrine hypothalamic-pituitary-gonadal (HHG) axis, involving hypothalamic GnRHs and the gonadotropic hormones FSH and LH, which emerged at the root of cartilaginous vertebrates. In addition, paracrine functions of GnRHs and thyrostimulin have been explored at the gonadic level in bony vertebrates. The aim of this thesis was to characterize the endocrine and paracrine regulation of spermatogenesis exerted by GnRHs and gonadotropic hormones in an Elasmobranch model, the catshark Scyliorhinus canicula. This work has been extended to the characterization of GPA2 and GPB5, constituting thyrostimulin, which correspond to orthologs of the molecular ancestors of glycoprotein hormone subunits. In this work, the evolution of the testicular proteome during spermatogenesis in S. canicula was described, and the neuropeptides GnRHs, the glycoprotein hormones FSH, LH, TSH, GPA2 and GPB5, as well as their associated receptors were studied by in silico and expression analyses in different tissues, with a focus on spermatogenesis. Expressions were observed at all stages of spermatogenesis for fshr, lhr and GnRH receptors associated at germinal and sertolian levels, for tshr and gpb5 at sertolian level and for gpa2 at germinal level, with higher abundances associated with spermatid stages. This work was complemented by in vitro functional tests which showed that FSHR could be activated by FSH and LH, LHR only by LH, and that GPB5-GPA2 could activate all three receptors FSHR, LHR and TSHR, suggesting a paracrine role for thyrostimulin at the testicular level. Taken together, this work proposes a model for the regulation of spermatogenesis in Elasmobranchs that combines endocrine hormones, with circulating GnRHs and gonadotropins, and paracrine hormones, with GPA2, GPB5 and steroids. This model appears consistent and intermediate in the evolution of spermatogenesis regulating systems, which has shift from predominantly paracrine regulation in non-vertebrate bilaterians to predominantly endocrine regulation in bony vertebrates, with the establishment of the hypothalamic-pituitary-gonadal axis

Dans ce travail, nous montrons tout d'abord une production de 1,25 (OH)2D3 par les cellules pulmonaires fraîchement recueillies par lavage bronchoalvéolaire (LBA) chez des sujets tuberculeux hypercalcémiques (annexe I). Ensuite, après avoir constaté une corrélation entre les capacités de production de la 1,25 (OH)2D3 par ces cellules alvéolaires et les anomalies du bilan phosphocalciques (annexe II), nous avons identifié les cellules responsables de cette production chez des sujets tuberculeux non hypercalcémiques (annexe III). Ainsi, nous avons montré qu'une activité 25(OH)D3-1-a-hydroxylase est toujours retrouvée dans les macrophages T pulmonaires alors qu'elle est inconstante dans les macrophages et paraît absente ou considérablement réduite dans les cellules circulantes. Parallèlement, nous avons montré qu'une fraction des lymphocytes T alvéolaires expriment le récepteur de la 1,25 (OH)2D3 au site de la tuberculose, récepteur absent des lymphocytes circulants (annexe IV). La poursuite de notre recherche dans ce domaine vise à apprécier les interactions entre la 1,25 (OH)2D3 et les cellules (lymphocytes, monocytes) produisant des médiateurs impliqués dans la formation et la régulation des activités du granulome (TNFa, PGE2, IGF1, gIFN. . . ) (annexes V-VII).

Afin de mieux comprendre leur histoire évolutive, nous avons recherché la présence de la CT, du CGRP et de leurs organes cibles, chez un téléostéen, Anguilla anguilla, et deux céphalopodes, Nautilus macromphalus et Sepia officinalis. Contrairement à l’anguille, aucune molécule biologiquement apparentée à la CT n’a été détectée chez les céphalopodes. La co-localisation du CGRP et de son récepteur dans le système nerveux central de l’anguille et de la seiche, suggère que ce peptide pourrait jouer un rôle de neuromédiateur ou neurotransmetteur comme décrit chez les mammifères. L’implication du CGRP dans les mécanismes de régulation ionique, de façon endocrine dans les branchies et autocrine/paracrine dans le système rénal, représenterait une fonction ancienne, partagée par les téléostéens et les céphalopodes. Il semble que le CGRP ait une origine ancestrale intervenue avant l’émergence des deutérostomiens. La CT constituerait un peptide apparu plus tardivement au cours de l’évolution.

Les cellules corticosurrenaliennes (cc) adultes et ftales, cultivees en presence de dexamethasone (d) ou de cortisol (f), produisent 3 a 6 fois plus d'ampc et 8 a 20 fois plus de glucocorticoides (g), en reponse a l'acth, que les cellules temoins. Au contraire, la culture des cc, en presence d'aminoglutethimide ou de ru 38486, se traduit par une diminution dose-dependante de la secretion d'ampc induite par l'acth. Les g elevent la reponse maximale en ampc mais ne modifient pas l'ed50 de l'acth; ils n'augmentent pas la reponse ampc a la forskoline. La reponse steroidogene des cc cultivees en presence de d, est dose-dependante et biphasique, avec un maximum a 10-8m de d. Les g augmentent la reponse steroidogene maximale a l'acth et diminuent son ed50. L'activite adenylate cyclasique membranaire est accrue par les g, en reponse a une stimulation par l'acth+ un analogue non hydrolysable du gtp (gpp (nh)p), lorsque les cellules sont cultivees en presence de d. La sous-unite catalytique de la cyclase et les sous-unites regulatrices gs et gi ne semblent pas affectees par les g, mais le nombre de recepteurs de l'acth est augmente par un traitement aux g. Les g sont necessaires a la translocation, stimulee par l'ampc, du cholesterol du cytoplasme vers la mitochondrie. L'originalite de ces resultats est de suggerer que les g sont directement impliques dans la maturation surrenale ftale et dans le maintien de l'etat de differenciation des cc adultes

Abstract Three decades ago, Salmon and Daughaday (1957) proposed that the growth-promoting action of growth hormone was mediated through secondary substances. The search for such factors led to the discovery of the insulin-like growth factors (IGFs). These were discovered as three different biological activities in plasma; the growth hormone-regulated, sulphation factor activity, the non-suppressible insulin-like activity, and multiplication-stimulating activity (Daughaday et al. 1972, 1987).

Abstract In 1973, we reported that the intraperitoneal (i.p.) administration of CCK to rats shortly before a test meal decreased the size of that meal (Gibbs et al. 1973a). The effect was obtained with an impure extract of CCK as well as with the synthetic C-terminal octapeptide CCK-8 (Gibbs et al. 1973b). The effect was dose-related and did not appear to be non-specific or toxic. On the basis of these results, we proposed that endogenous CCK released from the mucosal cells of the upper small intestine by food ingested during a meal acted to terminate that meal by a hormonal mode of action. We now believe that sufficient evidence has been obtained to consider the essence of the hypothesis proven although the mode of action of CCK- endocrine or paracrine- has not been settled. In this chapter, we review the evidence that we consider crucial. It comes from two kinds of experiments - experiments with agonists and experiments with antagonists.