The role of microRNAs in the pre-implantation mammalian embryo

Makri, K.D. (2021) The role of microRNAs in the pre-implantation mammalian embryo. PhD thesis, University of Nottingham.

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Abstract

MicroRNAs (miRNAs) are small non-coding RNA molecules that exert regulatory actions in gene expression acting mainly via RNA silencing and post-transcriptional changes. Their actions are involved in important cell processes such as stress signalling, cell cycle progression, differentiation, and cell death. Mammalian gametes and pre-implantation embryos selectively express miRNAs that control oocyte maturation, spermatogenesis, fertilisation, embryonic division and growth, development and differentiation, and implantation.

Blastocyst-stage embryos release miRNAs in the surrounding micro-environment and these can be quantified in vitro. The levels of specific cell-free miRNAs are linked to embryo aneuploidy and implantation outcomes in human assisted reproduction cycles.

However, there are no reports about the value of miRNAs as biomarkers of embryonic quality and their use for embryo (de-)selection purposes. Importantly, basic science evidence about the roles of secreted miRNAs at the peri-implantation period is lacking.

The main objective of this thesis is to investigate the biological reason that embryos differentially release specific miRNAs and whether miRNAs have effects on reproduction with specific focus on embryo-maternal communication at the pre-implantation period.

This was addressed firstly by analysing miRNAs in spent media samples from blastocysts and correlating their levels with embryo quality markers (apoptosis and morphokinetics). It was found that highly apoptotic mouse embryos release more miR-294 in spent media. Further research showed that it is the process of apoptosis which triggers the release of this miRNA. This finding was reproduced in bovine embryos where the homologue miR-371 was also linked to extensive blastomere apoptosis. Lastly, human endometrial cells were transfected with the miR-371 mimic and were analysed for transcriptomic changes using microarray technology. Global genome changes were caused by this miRNA which impaired processes related to implantation.

The original findings presented here suggest that miRNA analysis of individual spent media samples using current technology could be a valuable method for assessment of embryo quality. Potentially, miRNA analysis could be integrated in the future in multi-OMICS platforms for increasing the effectiveness of embryo (de-)selection for clinical purposes. The findings that apoptosis triggers the release of specific miRNAs from pre-implantation embryos which then cause major gene expression changes influencing implantation provide novel insights on the roles of miRNAs in reproduction. Ultimately, this thesis concludes that embryo-secreted miRNAs have key-roles in the communication between the embryo and the maternal cells and act as molecular cues to promote or impair implantation. Future research is advised to elucidate the miRNA molecular network at the embryo-maternal interface.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Maalouf, W.E.
Sinclair, K.
Keywords: MicroRNAs; Embryo-maternal communication; Pre-implantation period
Subjects: QS-QZ Preclinical sciences (NLM Classification) > QU Biochemistry
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID: 66336
Depositing User: Makri, Klaountia
Date Deposited: 31 Dec 2021 04:40
Last Modified: 31 Dec 2021 04:40
URI: http://eprints.nottingham.ac.uk/id/eprint/66336

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