Diferencijacija stanica trofoblasta u normalnoj i patološkoj trudnoći [Differentiation of human trophoblast cells in normal and pathological pregnancy]

Zmijanac Partl, Jasenka (2016) Diferencijacija stanica trofoblasta u normalnoj i patološkoj trudnoći [Differentiation of human trophoblast cells in normal and pathological pregnancy]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Differentiation of trophoblast cells is a process that involves an epithelialmesenchymal transition (EMT) in which components of the Wnt signaling pathways play a crucial role. SFRP1 and SFRP3 act as Wnt antagonists, tending to maintain the characteristics of epithelial cells while TCF1 is implicated in trophoblast cell invasion. The aim of this study was to analyse the expression of Wnt signaling pathway antagonists, SFRP1 and SFRP3 proteins, and its positive regulator TCF1 in normal and pathological placentas ( IUGR, hypertensive disorders, gestatonal diabetes). An independent marker of epithelial phenotype ELF5, was chosen to additionally confirm our findings. Immunohistochemical analysis demonstrated elevated levels of SFRP1 and SFRP3 in normal preterm compared to term placentas. Total levels of SFRP1 and SFRP 3 proteins were also increased in all groups of pathological placentas compared to term controls. Interestingly, there was no statistical difference between normal preterm and term IUGR and preeclamptic placentas. Placentas from pregnancies complicated by gestational diabetes showed lower expression of SFRP1 and SFRP3 in chorionic villi and higher total levels of TCF1, demonstrating a more expressed trophoblastic proliferation. Lower levels of SFRP3 were also found in chorionic villi of preterm pathological placentas compared to healthy placentas, while its expression in decidual tissue was similar to SFRP1. These findings suggest the involvement of SFRP3 in cell growth promotion of normal villous tissue and indicate that SFRP3 may play a dual role during placentation. ELF5 expression was lower in healthy preterm than in term placentas, indicating active EMT. Pathological preterm and term placentas showed significantly higher ELF5 levels compared to control groups. These findings establish ELF5 as a suppressor of EMT in pathological pregnancies. Our data support the theory in which Wnt pathway has a dynamic role in the pathogenesis of IUGR, hypertensive disorders and gestational diabetes. We also found significant association of ELF5 with pregnancy disorders which have been related to the regulation of trophoblastic invasion and differentiation. We can conclude that impaired regulation of the Wnt signalling pathways can disrupt tissue homeostasis and lead to different pregnancy-related diseases.

Abstract in Croatian

Diferencijacija trofoblasta je proces koji uključuje epitelno - mezenhimsku tranziciju (EMT) u kojoj ključnu ulogu igraju akteri signalnog puta Wnt. SFRP1 i SFRP3 su antagonisti Wnt signalnog puta koji nastoje održati epitelne karakteristike stanica dok je protein TCF1 zadužen za invaziju stanica trofoblasta. Cilj ovog istraživanja bio je ispitati izraženost antagonista signalnog puta Wnt, proteina SFRP 1 i SFRP3, u zdravim i patološkim posteljicama (IUGR, hipertenzivni poremećaji, gestacijski dijabetes) kao i izraženost pozitivnog regulatora istog signalnog puta, proteina TCF1. Odabirom nezavisnog biljega epitelnog fenotipa, proteina ELF5, dodatno se potvrdio dobiveni rezultat. Imunohistokemijskim metodama dobili smo jaču izraženost SFRP1 i SFRP3 u normalnim prijevremenim nego u terminskim posteljicama. Ukupna razina SFRP1 i SFRP3 antigena bila je povišena u posteljicama svih patoloških skupina u odnosu na terminske kontrole. Zanimljivo je, da nije bilo statistički značajne razlike između normalnih prijevremenih i terminskih IUGR i preeklamptičnih posteljica. U korionskim resicama posteljica iz trudnoća kompliciranih gestacijskim dijabetesom izraženost SFRP1 i SFRP3 bila je manja, dok je ukupna razina TCF1 bila povišena, što ukazuje na izraženiju proliferaciju trofoblasta. Niža razina proteina SFRP3 nađena je i u korionskim resicama prijevremenih patoloških posteljica u odnosu na zdrave dok mu je izraženost u decidui poput SFRP1. Ovakvi nalazi ukazuju na moguću ulogu SFRP3 u poticanju staničnog rasta u normalnom tkivu resica, odnosno na dvostruku ulogu SFRP3 tijekom placentacije. Ekspresija ELF5 manja je u zdravim prijevremenim nego u terminskim posteljicama što ukazuje na aktivnu EMT. U patološkim prijevremenim i terminskim posteljicama razina ELF5 značajno je veća u usporedbi s odgovarajućim kontrolama. Ovi nalazi potvrđuju ulogu ELF5 u supresiji EMT u patološkim trudnoćama. Naši nalazi podupiru teoriju prema kojoj Wnt ima dinamičnu ulogu u patogenezi IUGR, hipertenzivnih poremećaja i gestacijskog dijabetesa. Također smo utvrdili povezanost ELF5 s poremećajima trudnoće povezanim s neadekvatnom invazijom i diferencijacijom trofoblasta. Možemo zaključiti da poremećaj regulacije mreže signalnih puteva narušava homeostazu u posteljičnom tkivu i vodi do različitih bolesti vezanih uz trudnoću.

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