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An integrated investigation of oocyte developmental competence: expression of key genes in human cumulus cells, morphokinetics of early divisions, blastulation, and euploidy

  • C. Scarica
  • D. Cimadomo
  • L. Dovere
  • A. Giancani
  • M. Stoppa
  • A. Capalbo
  • F. M. Ubaldi
  • L. RienziEmail author
  • R. Canipari
Assisted Reproduction Technologies
  • 32 Downloads

Abstract

Purpose

To investigate the association of cumulus cell (CC)-related expression of a selected cluster of key genes (PTGS2, CAMK1D, HAS2, STC1, and EFNB2) with embryo development to blastocyst.

Methods

Exploratory study at a private clinic. Eighteen advanced maternal age patients were enrolled (37.3 ± 4.0 years). Seventy-five cumuli were collected, whose oocytes resulted in either developmental arrest (N = 33) or blastocyst formation (N = 42). The noninvasive CC gene expression was combined with time-lapse morphokinetic parameters and, for blastocysts, with qPCR-based aneuploidy testing on trophectoderm biopsies.

Results

The detection rate was 100% for all transcripts, but STC1 (96%) and CAMK1D (89%). Among amplified assays, CC mean expression levels of CAMK1D, PTGS2, and HAS2 were higher from oocytes that developed to blastocyst. No difference in CC key gene expression was reported between euploid (N = 21) and aneuploid (N = 21) blastocysts. Some timings of early embryo development were faster in embryos developing to blastocyst (time of pronuclei appearance and fading, division to two- and four-cells, first and second cell cycles). However, the generalized linear models outlined increasing CAMK1D expression levels as the strongest parameter associated with oocytes’ developmental potential from both a general (AUC = 0.78 among amplified samples) and an intrapatient perspectives (AUC = 0.9 among patients obtaining ≥ 2 zygotes from the cohort with different developmental outcomes).

Conclusions

CAMK1D level of expression in CCs associated with blastocyst development. If confirmed from larger studies in wider populations of patients, the investigation of CC key gene expression might suit IVF clinics not adopting blastocyst culture. Future investigations should clarify the role of CAMK1D in ovarian physiology and could provide novel insights on how oocytes gain competence during folliculogenesis.

Keywords

Oocyte competence Cumulus cells Blastocysts Noninvasive embryo selection CAMK1D 

Notes

Authors’ contribution

CS, DC, AC, LR, and RC designed the study. CS and DC collected and analyzed the samples. CS, DC, and RC drafted the manuscript. All authors contributed to the interpretation and discussion of the data.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10815_2019_1410_Fig4_ESM.png (62 kb)
Supplementary Figure 1

Mean Ct values forB2MandUBCin the cumulus cells from oocytes that underwent developmental arrest versus blastocyst formation. Mann-Whitney U tests were conducted that did not show any statistically significant difference. (PNG 62 kb)

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High resolution image (TIF 5501 kb)
10815_2019_1410_Fig5_ESM.png (85 kb)
Supplementary Figure 2

Geometric mean ofB2MandUBCCt values in the samples whereSTC1andCAMK1Dwere detected versus the samples where these key-genes were not detected. Mann-Whitney U tests were conducted. Effect size d and post-hoc power analyses were also reported. (PNG 84 kb)

10815_2019_1410_MOESM2_ESM.tif (5 mb)
High resolution image (TIF 5121 kb)
10815_2019_1410_Fig6_ESM.png (68 kb)
Supplementary Figure 3

Relative expression levels ofSTC1andEFNB2from the cumulus cells of developmentally incompetent versus competent oocytes. Total RNA was extracted from cumulus cells obtained from oocytes that resulted in either arrested embryos or blastocysts after IVF. Quantitative-PCR was conducted using Taqman primers. Each reaction was performed in triplicate. Each sample was normalized to its B2M and UBC mRNA content. The mean 2^-dCT values with SD and range are reported next to each boxplot. Mann-Whitney U tests were conducted to assess statistically-significant differences. No statistically-significant difference was defined. Circles and stars represent outliers values (PNG 67 kb)

10815_2019_1410_MOESM3_ESM.tif (4.8 mb)
High resolution image (TIF 4942 kb)
10815_2019_1410_Fig7_ESM.png (76 kb)
Supplementary Figure 4

Relative expression levels ofCAMK1D,PTGS2andHAS2from the cumulus cells whose oocytes developed as aneuploid versus euploid blastocysts (sub-analysis). Total RNA was extracted from cumulus cells obtained from oocytes that resulted in either aneuploid or euploid blastocysts after IVF. Quantitative-PCR was conducted using Taqman primers. Each reaction was performed in triplicate. Each sample was normalized to its B2M and UBC mRNA content. The mean 2^-dCT values with SD and range are reported next to each boxplot. Mann-Whitney U tests were conducted to assess statistically-significant differences. No statistically-significant difference was reported. Effect size d and post-hoc power analyses were also calculated. Circles and stars represent outliers values (PNG 76 kb)

10815_2019_1410_MOESM4_ESM.tif (3.2 mb)
High resolution image (TIF 3275 kb)
10815_2019_1410_Fig8_ESM.png (126 kb)
Supplementary Figure 5

Relative expression levels ofCAMK1D,PTGS2andHAS2from the cumulus cells of oocytes that developed as high quality (class 1&2) and low quality (class 3&4) blastocysts or underwent developmental arrest (sub-analysis). Total RNA was extracted from cumulus cells obtained from oocytes that resulted in either arrested embryos or blastocysts after IVF. Quantitative-PCR was conducted using Taqman primers. Each reaction was performed in triplicate. Each sample was normalized to its B2M and UBC mRNA content. The mean 2^-dCT values with SD and range are reported next to each boxplot. Mann-Whitney U tests were conducted to assess statistically-significant differences. Effect size d and post-hoc power analyses were also reported. Circles and stars represent outliers values (PNG 125 kb)

10815_2019_1410_MOESM5_ESM.tif (4.1 mb)
High resolution image (TIF 4236 kb)
10815_2019_1410_Fig9_ESM.png (90 kb)
Supplementary Figure 6

Patient-specific mean CCs’ expression of selected key-genes with 95%CI entailing all the samples that were amplified within each cohort of zygotes. Kruskal-Wallis tests were conducted to assess statistically significant differences (PNG 89 kb)

10815_2019_1410_MOESM6_ESM.tif (6 mb)
High resolution image (TIF 6171 kb)
10815_2019_1410_Fig10_ESM.png (115 kb)
Supplementary Figure 7

Receiver Operating Characteristic (ROC) curve analysis for the predictive power ofCAMK1D2^-dCT upon oocyte developmental competence in vitro from both a general (a) and a patient-specific (b) analyses conducted from this dataset. The former analysis entailed 67 of the 75 cumuli included in this study (89%), namely the samples where this transcript was detected; the latter analysis instead included the patients (N = 11) who obtained at least two oocytes from the cohort with opposite outcomes (arrested embryo and blastocyst development) and whose cumulus cells resulted in CAMK1D detection. AUC, area under the curve. (PNG 115 kb)

10815_2019_1410_MOESM7_ESM.tif (4.7 mb)
High resolution image (TIF 4831 kb)
10815_2019_1410_MOESM8_ESM.docx (18 kb)
Supplementary Table 1 (DOCX 17 kb)
10815_2019_1410_MOESM9_ESM.docx (31 kb)
Supplementary Table 2 (DOCX 31 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.DAHFMO, Unit of Histology and Medical EmbryologySapienza, University of RomeRomeItaly
  2. 2.Casa di cura Villa SalariaRomeItaly
  3. 3.Clinica Valle Giulia, G.EN.E.R.A. Centers for Reproductive MedicineRomeItaly
  4. 4.IgenomixMarosticaItaly

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