EMBRYO QUALITY PREDICTIVE MODELS BASED
ON CUMULUS CELLS GENE EXPRESSION
Devjak R, Burnik Papler T, Verdenik I, Fon Tacer K, Vrtačnik Bokal E
*Corresponding Author: Rok Devjak, M.D., Ph.D., Division of Medical Oncology, Institute of Oncology,
Zaloška 2, 1000 Ljubljana, Slovenia. Tel: +386-1-5879-282; Fax: +386-1-5879-303. E-mail: rdevjak@onko-i.si
page: 5
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INTRODUCTION
Since the introduction of in vitro fertilization
(IVF) in the clinical practice of infertility treatment,
indicators of implantation potential of embryos have
been researched. Despite significant improvements in
assisted reproductive technology (ART), the success
of IVF remains low. Although most of the oocytes
retrieved after ovarian stimulation with gonadotropins
in combination with gonadotro-pin-releasing hormone
(GnRH) analogues are capable of fertilization, only
half of them develop into embryos and even fewer implant
[1]. Therefore, to increase pregnancy rate, more
than one embryo is usually transferred, which can lead
to multiple pregnancies and increased fetal and maternal
morbidity and mortality [2]. Consequently, there
is a need for identifying biomarkers that would serve
as reliable indicators of high implantation potential
of the embryos available for transfer [3].
The selection of embryos for transfer is currently
based on the evaluation of subjective morphological
criteria. These include evaluation of pronuclei in
the zygote and early cleavage. On day 3 after oocyte
retrieval, the embryo fragmentation, number and morphology
of blastomeres, and the presence of multiple
nuclei are evaluated; on day 5, blastocyst morphology
is evaluated considering the Gardner and Schoolcraft
system [4]. The presence of a mature (MII) and highquality
oocyte plays an essential role in the development
of a high-quality embryo [5]. This means that the
selection of high-quality embryos begins at the time of
oocyte selection. The oocyte selection for fertilization
is currently also based on morphological evaluation
of the polar body, meiotic spindle, zona pellucida
and cytoplasm [6]. There is increasing evidence that
morphological evaluation is not a reliable predictor
of oocyte competence and embryo implantation potential
[7]; that is why there is a need to discover new,
noninvasive, objective and reliable indicators of oocyte
and embryo quality. Having reliable biomarkers
for oocyte and embryo selection could be of special
importance in selective embryo transfer to avoid a
twin pregnancy. Lately, the most intense research is
being carried out on genome analysis of cumulus cells
(CC) and granulosa cells (GC) in order to discover
biomarkers that would be predictive of oocyte and
embryo developmental potential [8-10].
It is well known that there is intense bidirectional
communication between oocytes and their surrounding
CC and GC through gap junctions and paracrine
signaling during folliculogenesis [11]. This communication
is crucial for the development of a mature,
developmentally competent oocyte. Instead of being
a passive recipient of nutrients and regulatory signals
from its surrounding CC and GC, the oocyte plays an
active role in the secretion of paracrine factors that
maintain an appropriate micro environment for the
acquisition of its developmental competence [12].
This leads to functional changes in CC and GC which
are crucial for the development of a quality oocyte
[13]. In clinical practice, this means that these cells
can serve as an indirect marker of oocyte quality. In
IVF procedures, these cells are separated from oocytes
and then discarded. They are easily accessible
and plentiful, which makes them a perfect material
for gene expression analysis in order to identify reliable
and objective biomarkers of oocyte quality and
embryo development potential [11].
Cumulus cells have been the subject of many
studies in order to test whether oocyte quality is related
to the expression of some of the growth differentiation
factor 9 (GDF9)-dependent genes (HAS2,
PTGS2 in PTX3) [3,14, 15]. Furthermore, CC have
been analyzed in terms of gene expression related to
the quality of embryo development. van Montfoort et
al. [9] proposed a set of the following genes: CCND2,
CXCR4, GPX3, CTNND1, DHCR7, DVL3, HSPB1
and TRIM28 that have proven to be most variably
expressed among the CC of the follicles with zygotes
that underwent a rapid division, and the CC of those
follicles the zygotes of which underwent a slow division
[9]. Hamel et al. [16] proposed the following set
of genes: FDX1, CYP19A1, CDC42, SERPINE2 and
3βHSD1 as those having the most variable expression
among the GC from the follicles that resulted
in pregnancy and those that did not.
In our previous study [10], we identified CC
expression of AMHR2, LIF, SERPINE2, VEGFC and
FSHR to be associated with blastocyst formation. In
that study, LIF did not pass correction for multiple
hypothesis testing, but due to its previous implication
for oocyte maturation [17], we included it in our further
analyses of CC expression. In this study, we used
these genes to construct an embryo quality outcome
model according to CC gene expression from oocytes
that resulted in either high or low quality embryos.
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