The outer surface of the human placenta, the syncytiotrophoblast, results from the fusion of many cytotrophoblast cells such that many nuclei are contained in this layer. It is possible for these nuclei to cluster forming syncytial nuclear aggregates (SNAs). SNAs have been linked to pathology with increased numbers and earlier formation of SNAs in preeclampsia and fetal growth restriction (FGR). SNAs can be grouped into subtypes including bridges, knots and sprouts, dependent on morphology and attachment to surrounding placental villi. Little is known about SNA formation, but the pyknotic appearance of nuclei within SNAs has led to development of a hypothesis that SNAs are the terminal point of nuclear turnover in the syncytiotrophoblast. Some cytoskeletal proteins have been associated with SNAs indicating their potential involvement in SNA formation. This project aimed to uncover differences between SNA subtypes, whether the degenerate nuclear morphology represents apoptosis and to understand which mechanisms drive nuclear collection into SNAs. Experimental approaches included a review of an electron micrograph archive and application of immunohistochemical techniques to ex vivo placental tissue. A long-term explant model was developed to examine SNA development in vitro; these experiments were further explored using an isolated primary cytotrophoblast model. Nuclei within SNAs were more frequently pyknotic and less frequently eukaryotic than nuclei dispersed in the syncytiotrophoblast. However, few SNAs were positive for the cytokeratin-M30 neoepitope, a caspase dependent breakdown product of cytokeratin-18 and no subtype of SNA showed greater M30 staining than general areas of syncytiotrophoblast. There were increased syncytial knots and decreased syncytial bridges in placentas from women with preeclampsia compared to controls and FGR. While cytoskeletal proteins are seen surrounding SNAs, inhibition of actin and tubulin had no effect on SNA turnover or stability. Very limited nuclear movement was recorded from in vitro culture indicating that syncytiotrophoblast nuclei move far less than had been expected. These data suggest that cell death was not prominent within SNAs but different prevalence of subtypes were present in preeclampsia indicating that SNAs might represent larger changes in placenta structure. As nuclei moved less and SNAs were more static than expected it is suggests that SNAs are more stable than previously thought. Overall, the hypothesis that SNAs are highly active in preeclampsia is questioned and new hypotheses of the role of SNAs are considered in the light of these experimental findings, including whether they form by chance and represent changes in cell turnover of the syncytiotrophoblast.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:607049 |
| Date | January 2013 |
| Creators | Calvert, Sarah Joyce |
| Contributors | Aplin, John; Sibley, Colin; Heazell, Alexander |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/an-investigation-into-the-mechanisms-of-syncytial-nuclear-aggregate-formation(5654b3eb-72fe-4e86-ba7b-e0574c70c27e).html |
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