ESR Blog post #1 "Introducing the study of an improved human in vitro maturation (IVM) system" by Berta Cava, ESR 13

Hello everybody! I am Berta Cava Cami, ESR 13 and I would like to introduce my PhD project focused on the development and safety analysis of an improved human in vitro maturation (IVM) system by the addition of oocyte secreted factors (OSFs).

IVM is an alternative assisted reproductive technology (ART) where immature Cumulus Oocyte Complexes (COCs) from antral follicles are collected with no or minimal stimulation of the ovaries and are matured in vitro (De Vos et al., 2016). IVM can be offered to women which have a high risk of ovarian hyperstimulation syndrome (OHSS) such as Polycystic Ovary Syndrome (PCOS) patients, eliminating this risk. IVM can also be offered to cancer patients who require urgent fertility preservation and do not have time to undergo controlled ovarian stimulation (COS) or suffer from oestrogen-sensitive cancers in which COS is contra indicated. In addition, IVM would be an option for these patients who do not respond to stimulation protocols where the retrieval of in vivo matured oocytes is not possible. IVM presents important advantages compared to conventional in vitro fertilization (IVF) such as a reduced medication cost, lower treatment burden and lower monitoring needs. However, live birth rates after IVM are currently lower than with IVF (Walls et al., 2015) so that research is focusing on the further improvement of IVM conditions.

One of the recent improvements in IVM is the development of a biphasic IVM culture termed capacitation (CAPA)-IVM (Romero et al., 2016). The aim of adding a pre-maturation step is to allow the successful synchronization of meiotic and cytoplasmic maturation with C-type Natriuretic peptide (CNP). CNP binds to its receptor (NPR2) in cumulus cells and prevents the spontaneous meiosis resumption by maintaining high levels of cAMP inside the oocyte.

The use of CAPA-IVM has been already investigated in humans increasing the number of matured oocytes (62-70 vs 48%) and subsequent good quality blastocyst rate compared to standard IVM. (Sánchez et al., 2017; Sánchez et al., 2019; Vuong et al., 2019). However, there is still a gap in terms of efficiency between CAPA-IVM and conventional IVF.

Based on different animal models studies, addition of oocyte-secreted factors (OSFs) promotes cumulus cells proliferation and maintains the cumulus phenotype which in turn, improves the developmental competence of IVM oocytes. Moreover, immature oocytes from small antral follicles may be deficient in OSF. Therefore, adding OSFs into the maturation media could improve the developmental competence of human oocytes as seen in animal models. Two of the most crucial OSFs are Growth Differentiation Factor 9 (GDF9) and Bone Morphogenetic Protein 15 (BMP15) which are secreted as proproteins and need a proteolytic cleavage to become active. OSFs exist as homodimers and due to their similar sequence can interact (Liao et al 2003) and form a functional heterodimer (Peng et al., 2013; Mottershead et al 2015) termed Cumulin. Therefore, we aim to test if the addition of Pro-Cumulin improves the developmental competence of in vitro CAPA-IVM oocytes by studying the transcriptomic and epigenetic profile of paired cumulus-oocytes and by evaluating the cytoplasmic maturation assessing organelle distribution with fluorescence confocal cell imaging approaches.