Diferencijacija stanica trofoblasta u normalnoj i patološkoj trudnoći

doctoral thesis

• Title (english): Differentiation of human trophoblast cells in normal and pathological pregnancy
• Author: Jasenka Zmijanac Partl
• Mentor: Ljiljana Šerman (mentor)
• Committee member: nije dostupno (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; Zagreb
• Defense date and country: 2016-06-09, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences
• Universal decimal classification (UDC): 61 - Medical sciences

Abstract

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.

Abstract (english)

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.

• Keywords: medicina
• Keywords (english): medicine
• Language: croatian
• URN:NBN: urn:nbn:hr:105:278538
• Study programme: Title: Biomedicine and Health Sciences; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstva (doktor/doktorica znanosti, područje biomedicine i zdravstva)
• Type of resource: Text
• Extent: 196 str.
• File origin: Born digital
• Access conditions: Open access
• Created on: 2023-05-05 08:41:55