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“Cumulome” Reveals Major Metabolic Aberrations After Maturation in Vitro

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“Cumulome” Reveals Major Metabolic Aberrations After Maturation in Vitro Walter et al. BMC Genomics (2019) 20:588 https://doi.org/10.1186/s12864-019-5836-5 RESEARCHARTICLE Open Access Analysis of the equine “cumulome” reveals major metabolic aberrations after maturation in vitro Jasmin Walter1* , Fabian Huwiler1, Claudia Fortes2, Jonas Grossmann2, Bernd Roschitzki2, Junmin Hu2, Hanspeter Naegeli3, Endre Laczko2 and Ulrich Bleul1 Abstract Background: Maturation of oocytes under in vitro conditions (IVM) results in impaired developmental competence compared to oocytes matured in vivo. As oocytes are closely coupled to their cumulus complex, elucidating aberrations in cumulus metabolism in vitro is important to bridge the gap towards more physiological maturation conditions. The aim of this study was to analyze the equine “cumulome” in a novel combination of proteomic (nano-HPLC MS/MS) and metabolomic (UPLC-nanoESI-MS) profiling of single cumulus complexes of metaphase II oocytes matured either in vivo (n = 8) or in vitro (n = 7). Results: A total of 1811 quantifiable proteins and 906 metabolic compounds were identified. The proteome contained 216 differentially expressed proteins (p ≤ 0.05; FC ≥ 2; 95 decreased and 121 increased in vitro), and the metabolome contained 108 metabolites with significantly different abundance (p ≤ 0.05; FC ≥ 2; 24 decreased and 84 increased in vitro). The in vitro “cumulome” was summarized in the following 10 metabolic groups (containing 78 proteins and 21 metabolites): (1) oxygen supply, (2) glucose metabolism, (3) fatty acid metabolism, (4) oxidative phosphorylation, (5) amino acid metabolism, (6) purine and pyrimidine metabolism, (7) steroid metabolism, (8) extracellular matrix, (9) complement cascade and (10) coagulation cascade. The KEGG pathway “complement and coagulation cascades” (ID4610; n = 21) was significantly overrepresented after in vitro maturation. The findings indicate that the in vitro condition especially affects central metabolism and extracellular matrix composition. Important candidates for the metabolic group oxygen supply were underrepresented after maturation in vitro. Additionally, a shift towards glycolysis was detected in glucose metabolism. Therefore, under in vitro conditions, cumulus cells seem to preferentially consume excess available glucose to meet their energy requirements. Proteins involved in biosynthetic processes for fatty acids, cholesterol, amino acids, and purines exhibited higher abundances after maturation in vitro. Conclusion: This study revealed the marked impact of maturation conditions on the “cumulome” of individual cumulus oocyte complexes. Under the studied in vitro milieu, cumulus cells seem to compensate for a lack of important substrates by shifting to aerobic glycolysis. These findings will help to adapt culture media towards more physiological conditions for oocyte maturation. Keywords: Oocyte, Cumulus, IVM, Proteomics, Metabolomics, Complement, Coagulation, Glucose, Oxygen, Purine * Correspondence: [email protected] 1Clinic of Reproductive Medicine, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Walter et al. BMC Genomics (2019) 20:588 Page 2 of 24 Background transcriptome between in vitro and in vivo matured Maturation of oocytes is the first step for in vitro pro- COCs [31–34]. All these studies were performed in spe- duction (IVP) of embryos across species. Oocyte matur- cies other than the horse. An equine study on granulosa ation can occur under in vivo conditions where mature cells, which have a developmental origin similar to that oocytes are collected from the donor for fertilization or of cumulus cells, observed age-related changes in their under in vitro conditions. Usually, maturation in vitro is transcriptome [35]. Another transcriptomic study on accompanied by decreased developmental competence equine granulosa and theca cells during dominant among oocytes [1, 2]. The standard in vitro fertilization follicular development identified distinct expression (IVF) protocol in human reproduction includes the ovar- profiles within these stages [36]. ian stimulation of women with exogenous gonadotropins Studies focusing more closely on metabolism and the to mature oocytes in vivo [3]. Even though maturation CC phenotype, e.g., using proteomics or metabolomics, and fertilization rates after in vitro maturation (IVM) are are rare. One major limitation for the proteomics promising, IVM correlates with decreased implantation approach is the large amount of COCs required for rates, increased miscarriage rates and increased live birth analysis [37, 38] as enrichment of proteins prior to ana- rates [3–5]. Therefore, candidates for IVM in human lysis is not possible. However, technical improvements reproduction are mostly restricted to women at risk for for these techniques currently allow the analysis of small ovarian hyperstimulation syndrome (OHSS) [3, 6]. For sample amounts [33, 39, 40]. Differences in the cumulus the equine species, direct comparisons of embryonic proteome through maternal ageing in humans [41], development after in vivo and in vitro are available. In between cyclic and prepubertal whole porcine COCs one study in vitro matured oocytes were transferred into [42, 43], and bovine cumulus cells and oocytes [44] were the oviduct for in vivo fertilization and further develop- reported in studies using pooled CCs or COCs. How- ment. The results showed a highly decreased develop- ever, beyond some practical benefits, pooling samples mental capacity of the in vitro matured oocytes (9%) has some drawbacks such as masking of outliers, dilu- compared with that of the in vivo matured oocytes tion of low abundance proteins and the loss of the possi- (82%) [1]. Blastocyst rates after intracytoplasmic sperm bility for the estimation of inter-individual variations injection (ICSI) of in vitro matured oocytes achieved within groups [45, 46]. These issues lead to the reduced only up to 35%, which was distinctly lower than their in applicability of pooled samples, especially for biomarker vivo matured counterparts (up to 70%) [2]. A special discovery [47]. Global protein expression profiling, with- mystery in equine-assisted reproduction is the complete out identification of altered protein spots, for human failure of classical IVF [7]. At present, this failure is cumulus cells of single oocytes was performed in 2006 reflected by only two foals born after classical IVF that [48]. This previous study observed alterations in the originated from oocytes matured in vivo [8, 9]. All other protein expression profiles of cumulus cells under equine IVP foals have been generated by ICSI [10, 11]. different stimulation protocols, as well as minor aberrations Whether the cause of this issue is located on the male or in fertilization outcomes using protein electrophoresis female side currently remains unclear [7, 12]. after metabolic labelling [48]. Only recently, intact- Available clinical data reflect the gap between in vitro cellMALDI-TOF mass spectrometry (ICM-MS) in matured and in vivo matured oocytes with regard to the combination with top-down proteomics was investigated developmental competence of oocytes. Fundamental as tool for biomarker discovery in cumulus cells of single research to elucidate altered metabolism during IVM is bovine oocytes [49]. Data on the equine cumulus cell necessary to bridge this gap. Currently, high-throughput proteome are not available in the literature. However, a “Omics” technologies provide the opportunity to obtain characterization of the mare follicular fluid composition a more global view on complex biological processes in was performed during late follicular development using reproduction [13–16]. The cumulus complex (CC) 2D-PAGE and mass spectrometry [50]. Similar metho- makes intimate contact with its oocyte and is required dology was used to characterize seasonal variation in to obtain the maturational competence of the oocyte equine follicular fluid [51]. [17–21]. After maturation and fertilization, the CC is Data on the cumulus cell metabolome are even scarcer not required for further development; thus, these cells across species. Comparison of in vitro matured with in vivo can serve as a unique source to noninvasively investigate matured COCs revealed altered cellular metabolism-related metabolism during oocyte maturation [22]. Most of the genes along with increased triglycerides in bovine cumulus available “Omics” studies on cumulus cells are transcrip- cells matured in vitro [34]. Glycosidic residues showed tomic analyses of pooled cumulus or cumulus oocyte significant quantitative and qualitative differences in equine complexes (COCs) that relate the gene expression profile and porcine COCs after in vitro and in vivo maturation to the developmental competence of the oocyte [23–30]. [52]. In the horse, maternal obesity caused alterations in Other studies examined changes in
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