The molecular interactions between trophoblast and endometrial cells in embryo implantation
Date
2023-10-02
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Abstract
Uue elu algus ja rasedus võivad esmapilgul tunduda üks loomulikumaid etappe naise elus, samas on see osutunud paljude paaride jaoks tõsiseks proovikiviks. Kuigi kehavälise viljastamise abiga sünnib igal aastal üha enam lapsi, siis endiselt ei õnnestu paljudel naistel seeläbi rasestuda. Mõistetavatel eetilistel põhjustel ei ole inimese embrüo pesastumist võimalik uurida naise organismis, seega on alternatiivsed uuringud vajalikud, mõistmaks mehhanisme, mis reguleerivad embrüo kinnitumist. Käesolev doktoritöö keskendub molekulaarsele suhtlusele endomeetriumi ja embrüo trofoblasti rakkude vahel. Kirjeldab naise endomeetriumi koe küpsemist ning selle protsessi seost geeniekspressiooni mustri muutustega kahes põhilises endomeetriumi rakutüübis - strooma ja epiteeli rakkudes. Selle uuringu põhjal töötati välja uus geenide aktiivsuse analüüsi meetod, mille abil määratakse endomeetriumi retseptiivsuseks oluliste RNA molekulide taset, eesmärgiga leida viljatusravi saava naise jaoks embrüo siirdamiseks parim aeg. Põhinedes rakutüübi-põhistele geenide avaldumise andmetele kirjeldati ligikaudu 550 valk-valk seost, mis moodustavad molekulaarse võrgustiku embrüo ja endomeetriumi rakkude vahel ning on vajalikud uue elu alguseks. Lisaks embrüo kinnitumisele on raseduse edukaks lõpuni kandmiseks vajalik õigesti arenev platsenta, mis võimaldab lootel normaalselt kasvada ja areneda. Selleks on määrava tähtsusega trofoblasti rakkude diferentseerumine. Doktoritöös uuriti inimese embrüonaalsete tüvirakkude diferentseerimise meetodeid trofoblasti-sarnasteks rakkudeks läbi BMP4 signaaliraja aktiveerimise ja TGBβ ja FGF2 signaaliradade inhibeerimise. Siin esitatud teadmised on oluliseks panuseks tulevastesse reproduktiivuuringutesse. Luues uusi võimalusi embrüo edukaks siirdamiseks ning uute prognostiliste ja diagnostiliste biomarkerite arendamiseks, mida kasutada viljatuse diagnostikas ning ravi optimeerimises.
Embryo implantation is a complex process in human reproduction, requiring precise coordination between maternal cells and the developing embryo. The receptive state of the endometrium, known as the "window of implantation," is crucial for successful embryo attachment. Despite the naturalness of pregnancy, infertility remains a significant challenge for many couples. Ethical limitations on in vivo studies hinder a comprehensive understanding of the implantation process, requiring alternative approaches. This doctoral thesis investigates the molecular communication between endometrial cells and embryonic trophoblasts. It elucidates the maturation process of the female endometrial tissue and its correlation with changes in gene expression patterns in the two primary types of endometrial cells: stromal and epithelial cells. Drawing from this study, a novel method for analyzing gene activity was developed to determine the levels of crucial RNA molecules associated with endometrial receptivity to identify the optimal timing for embryo transfer in women undergoing infertility treatment. Based on cell type-specific gene expression data, approximately 550 protein-protein interactions were characterized, forming a molecular network between the embryo and endometrial cells essential for initiating new life. Additionally, proper placenta development is crucial for a successful pregnancy, relying on trophoblast cell differentiation to support fetal growth and function. The thesis explores techniques to differentiate human embryonic stem cells into trophoblast-like cells, targeting the BMP4 signaling pathway while inhibiting TGFβ and FGF2 pathways crucial for placental formation. The knowledge generated through this research contributes to future advancements in reproductive research. It opens new possibilities for improving embryo transfer success rates and provides insights for developing prognostic and diagnostic biomarkers for infertility diagnosis and treatment optimization.
Embryo implantation is a complex process in human reproduction, requiring precise coordination between maternal cells and the developing embryo. The receptive state of the endometrium, known as the "window of implantation," is crucial for successful embryo attachment. Despite the naturalness of pregnancy, infertility remains a significant challenge for many couples. Ethical limitations on in vivo studies hinder a comprehensive understanding of the implantation process, requiring alternative approaches. This doctoral thesis investigates the molecular communication between endometrial cells and embryonic trophoblasts. It elucidates the maturation process of the female endometrial tissue and its correlation with changes in gene expression patterns in the two primary types of endometrial cells: stromal and epithelial cells. Drawing from this study, a novel method for analyzing gene activity was developed to determine the levels of crucial RNA molecules associated with endometrial receptivity to identify the optimal timing for embryo transfer in women undergoing infertility treatment. Based on cell type-specific gene expression data, approximately 550 protein-protein interactions were characterized, forming a molecular network between the embryo and endometrial cells essential for initiating new life. Additionally, proper placenta development is crucial for a successful pregnancy, relying on trophoblast cell differentiation to support fetal growth and function. The thesis explores techniques to differentiate human embryonic stem cells into trophoblast-like cells, targeting the BMP4 signaling pathway while inhibiting TGFβ and FGF2 pathways crucial for placental formation. The knowledge generated through this research contributes to future advancements in reproductive research. It opens new possibilities for improving embryo transfer success rates and provides insights for developing prognostic and diagnostic biomarkers for infertility diagnosis and treatment optimization.
Description
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Keywords
trophoblast, endometrium, molecular interaction, embryo transfer, implantation, molecular mechanisms, artificial fertilization, intercellular communication