In conclusion, the specific spatiotemporal expression patterns of galectin-1, -3, -4 and -9 in the bovine uterus and placenta throughout gestation suggests their involvement in placentation and maintenance of pregnancy. Moreover, differences in the expression depending on the immunological status of the cow lead to the assumption that galectins could be involved in the development of postpartal diseases. Our results stress the need of further in vitro experiments to elucidate the exact function of this protein in the placentome.
7 Summary
Rebecca Froehlich Galectin expression in the bovine uterus and placenta through the course of pregnancy with focus on the peripartal period
Galectins, lectins with beta-galactosidase affinity, play important regulatory roles in cell adhesion, proliferation and migration and are involved in the modulation of the adaptive and innate immunity. These proteins are promising candidates for participating in placentation processes, maintenance of pregnancy and local immune regulation in the uterus. To provide a base for future functional analysis galectin fingerprinting was performed for interplacentomal endometrium and placenta during bovine gestation. Special interest was paid to the prepartal period in connection with the serum-IGF-1 level of the cow.
In the past it was demonstrated that in dairy cows a severe negative energy balance, indicated by lower levels of serum IGF-1, could be associated with elevated inflammation markers in the endometrium and subsequently a higher incidence of postpartum metritis. Therefore the second objective of this study was to investigate if the local galectin expression is influenced by different IGF-1 serum levels.
For the galectin fingerprinting placentomal (P) and interplacentomal tissue (IP) was collected at a slaughterhouse and assigned to three stages of pregnancy: early gestation (day 30-130, n=9); mid gestation (day 130-220, n=7); late gestation (day 220-275, n=7). The collected samples were snap-frozen or fixed in Bouin’s solution and embedded in paraffin. The mRNA level gene expression for galectin-1, -3, -4 and -9 in late gestational stages was examined by RTq-PCR. The protein localisation was investigated by immunohistochemistry. Antibody specifity has been proven by Western Blotting.
For the characterisation of the prepartal period 17 clinically healthy, pregnant cows from the same farm and with similar body condition were chosen and grouped according to their IGF-1 blood levels into an IGF high (n=9) and an IGF low group (n=7 IGF-1<140ng/ml). A caesarean section was performed on day 275 after artificial insemination where two placentomes (P) and interplacentomal uterine tissue (IP) were sampled. Gene expression at mRNA level was investigated for galectin-1, -3,
-4, -9 and -13 by RT-qPCR and at the protein level for galectin-1, -3, -4 and -9 by immunohistochemistry
The mRNA expression of galectin-1, -3, -4 and -9 could be demonstrated in late gestational P and IP. Through gestation galectin-1 was mainly localised in vessel walls and stroma while galectin-3 showed a distribution in epithelia and the fetal mesenchyme. Similarly to galectin-3, galectin-4 and galectin-9 showed an epithelial localisation pattern with an additional expression of galectin-4 in stroma and vessel walls. Galectin-9 was not detectable in midgestational P but showed strongly stained granules in TGC in late gestational P.
In the prepartal period galectin-9 mRNA expression was significantly higher in IP (p< 0.05) in IGF high animals. Additionally galectin-13 showed a highly significant higher and galectin-4 a trend of higher (p<0.1) expression in IGF high animals. No difference in expression occurred in P as well as in P and IP for galectin-1 and galectin-3. Only slight changes were detectable on the protein level for all analysed molecules.
The expression and distinct localisation patterns with spatiotemporal changes indecates a function of galectins in the bovine uterus and placenta. Especially the different expression in IGF high and IGF low cows suggest that galectins might be involved in the local immune regulation and therefore have an impact on the incidence of postpartal diseases.
This study clearly indicates that galectins are promising candidates to be involved in maintenance of pregnancy, placentation and local uterine immunity. Therefore, it can be a base for further investigations on the actual galectin functions in the bovine placenta.
8 Zusammenfassung
Rebecca Fröhlich Galektinexpression im bovinen Uterus and Plazenta im Verlauf der Trächtigkeit mit spezieller Betrachtung der präpartalen Phase
Galektine spielen eine wichtige Rolle in der Regulation biologischer Prozesse wie Zell-Adhäsion, Proliferation und Migration, sowie in der Modulation der angeborenen als auch der erworbenen Immunität. Es ist daher wahrscheinlich, dass Galektine auch an der Steuerung der Plazentation, dem Erhalt der Trächtigkeit und der lokalen Immunregulation im bovinen Uterus maßgeblich beteiligt sind. Um eine Basis für zukünftige Untersuchungen zu liefern, war das erste Ziel dieser Studie ein Galektinprofil für das interplazentomäre Endometrium und das Plazentom während der Trächtigkeit des Rindes zu erstellen. Besondere Aufmerksamkeit galt der präpartalen Phase und dem immunolgischen Status der Kuh. In den letzten Jahren konnte gezeigt werden, dass eine schwere negative Energiebilanz während der Trächtigkeit, sichtbar durch erniedrigte IGF-1 Serumspiegel bei Milchkühen, in vermehrten Entzündungszeichen im postpartalen Uterus sowie einer höheren Inzidenz an postpartalen Erkrankungen resultiert. Daher war es ein weiteres Ziel dieser Studie zu untersuchen, ob die lokale Galektinexpression auf mRNA- und Proteinebene von unterschiedlichen IGF-Serum-spiegeln beeinflusst wird.
Für die Erstellung eines Galektinprofils wurden am Schlachthof Gewebeproben von interplazentomalem (IP) und plazentomalem (P) Bereichen des Uterus trächtiger Kühe verschiedener Stadien genommen und mittels Scheitel-Steiß-Länge in 3 Gruppen eingeteilt: Frühe Trächtigkeit (Tag 30-130, n=9); Mittlere Phase der Trächtigkeit (Tag 130-220, n=7); Späte Trächtigkeit (Tag 220-275, n=7). Die Proben wurden nach der Entnahme in flüssigem Stickstoff bzw. in Bouin’scher Lösung fixiert.
Galektin-1, -3, -4 und -9 wurden immunhistochemisch lokalisiert. Proben der späten Trächtigkeit wurden auch auf mRNA-Ebene mittels RT-qPCR untersucht. Die Spezifität der benutzen Antikörper konnte mittels Western Blot gezeigt werden.
Zur Charakterisierung der präpartalen Periode wurden 17 gesunde, trächtige Kühe von einem Milchviehbetrieb ausgewählt und anhand präpartaler IGF-1 Serumwerte in eine IGF-1 high (n=10; IGF-1>140ng/ml) und IGF-1 low (n=7; IGF-1< 140ng/ml)
Gruppe eingeteilt. Im Rahmen von Kaiserschnitten am 275.Tag der Trächtigkeit wurden Proben aus dem IP sowie zwei Plazentome entnommen. Die Analyse der Genexpression erfolgte für Galektin-1, -3, -4, -9 und -13 auf mRNA-Ebene mittels RT-qPCR und auf Proteinebene (mit Ausnahme von Galektin-13) mittels Immunhistochemie.
Für alle untersuchten Galektine konnte eine Expression im IP und im P während der Trächtigkeit auf mRNA-Ebene dargestellt werden. Galektin-1 zeigte eine Lokalisation im maternalen Stroma und den Gefäßwänden, sowie im plazentomalen Gewebe im Karunkelepithel. Dagegen konnte Galektin-3 hauptsächlich im Drüsenepithel, dem maternalen Epithel und dem fetalen Stroma nachgewiesen werden. Galektin-4 und -9 zeigten, ähnlich zu Galektin-3, eine Verteilung in den Epithelien, wobei Galektin-4 zusätzlich im Stroma und den Gefäßwänden zu finden war. Galektin-9 konnte in der mittleren Phase der Trächtigkeit nicht im P lokalisiert, jedoch in der späten Phase in Granula der TGC.
In der präpartalen Periode zeigte Galektin-13 eine hoch signifikant (p<0,001), Galektin-9 eine signifikant (p<0,05) erhöhte Expression und Galektin-4 den Trend (p<0,1) einer stärkeren Expression im interplazentomalen Gewebe von IGF-1 high Kühen, während die Galektin-1 und -3 Expressionen in beiden Untersuchungsgruppen gleich hoch waren. Im Plazentom konnten für keines der untersuchten Galektine Unterschiede zwischen den Gruppen festgestellt werden. Auf Proteinebene zeigten sich leichte Unterschiede in der Immunreaktivität.
Die Expression der Galektine sowie deren spezifische Lokalisation mit ihren Änderungen im Verlauf der Trächtigkeit deutet darauf hin, dass diese Proteine an Regulationsprozessen im bovinen Uterus beteiligt sind. Insbesondere die Expressionsunterschiede zwischen IGF high und low Kühen sind ein Hinweis darauf, dass Galektine an der Regulation der lokalen Immunantwort im Uterus beteiligt sein könnten. Diese Studie sollte als Basis für künftige Untersuchungen genutzt werden, in denen die genaue Funktion der Galektine im bovinen Uterus, beispielsweise am Zellkulturmodell, im Mittelpunkt stehen wird.
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