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Title: Immunological modification of placental syncytialization in humans
Author: Quilang, Rachel
ISNI:       0000 0004 8500 8617
Awarding Body: University of the West of Scotland
Current Institution: University of the West of Scotland
Date of Award: 2018
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Placental syncytialization, a process of cell-to-cell fusion, is essential to successful development of the placenta. Key to this fusion event are the cytotrophoblast cells, which differentiate and fuse into a multinucleated syncytiotrophoblast layer, forming the barrier between fetal and maternal cells. Understanding the cellular and molecular mechanisms that are involved in its regulation are not fully understood. This is important, as impaired syncytialization has been associated with placental dysfunction and infection. One such pathogen, Toxoplasma gondii (T. gondii) is able to cross the placenta and cause congenital toxoplasmosis in the fetus. It is unknown how this parasite is able to cross the placental barrier, but more importantly we do not fully understand the impact the parasite has on placental mechanisms, such as syncytialization. Thus, the ultimate aim of this thesis was to further understand the immunological modification of placental syncytialization in humans. The aim of chapter 2 was to establish an in vitro model of syncytialization using the choriocarcinoma cell line, BeWo cells. Disparity in the literature regarding the concentrations and length of exposure to the cAMP stimulator forskolin, to induce syncytialization in BeWo cells meant that it was crucial to optimise these conditions and establish syncytialization through the analysis of key markers (syncytin-1 and dysferlin). Interestingly, in doing so, the novel finding that these genes are expressed in a time-dependent manner has important implications for our understanding and interpretation of studies examining syncytialization. The aim of chapter 3 was to assess the atypical chemokine receptor 2 (ACKR2) expression in placental trophoblasts and BeWo cells. The majority of studies investigating ACKR2 in the placenta focus on its functional role in limiting the bioavailability of chemokines, but no studies have examined the relationship between syncytialization and ACKR2. BeWo cells induced to syncytialize by forskolin revealed the novel finding that ACKR2 mRNA is expressed in a timedependent manner and is associated with syncytialization. Induction of ACKR2 by forskolin has not been previously reported and may be of therapeutic value in its controlled expression in tissues where there is impaired inflammatory resolution. The aim of chapter 4 was to assess the effects of toll-like receptor (TLR) stimulation in both primary trophoblasts and BeWo cells by modelling T. gondii innate stimulation, with TLR2 and TLR4 agonists. Presence of TLR mRNA was detected in both primary trophoblast cells and BeWo cells. Differential expression of TLRs were found among the two cell types, with increased expression of CC chemokines in response to LPS. This study provides novel insight into the differences between primary trophoblast cells and immortalized cells, which contribute to understanding of how the placenta regulates inflammatory responses. The aim of chapter 5 was to assess the effect T. gondii infection had on primary trophoblasts and BeWo cell syncytialization, and if infection modulated TLR and ACKR2 expression. ACKR2 limits inflammation by degrading chemokines, which otherwise drive inflammation. However, no studies have investigated the role of ACKR2 during T. gondii infection, or if infection modulates syncytialization. Results showed that T. gondii invasion and replication rates were affected by host cell type. While syncytin-1 and dysferlin were unchanged by T. gondii, TLR4 mRNA was modulated by T. gondii in differentiated BeWo cells. Of significance, infected DMSO treated BeWo cells had increased expression of TLR4 and ACKR2 mRNA. These novel results have important implications for our understanding of congenital disease and pregnancy complications where inflammation is an underlying factor. In conclusion, the results within this thesis have demonstrated that placental syncytialization can be immunologically modified. This is of great importance to understanding the etiology of placental disorders and infections, where inflammation and syncytial impairment are contributing factors.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available