Cumulus cell gene expression predicts better cleavage-stage embryo or blastocyst development and pregnancy for ICSI patients

Wathlet, Sandra; Adriaenssens, Tom; Segers, Ingrid; Verheyen, Greta; Velde, H. Van de; Coucke, Wim; El, Rabotnikova; Devroey, Paul; Smitz, Johan

doi:10.1093/humrep/der036

Cited by 121 publications

(127 citation statements)

References 34 publications

(41 reference statements)

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“…The 4-fold down-regulation of GREM1 gene expression seen may indicate impaired oocyte function and cumulus GC expansion, associated with poor reproductive outcome. It has been previously shown that increased GREM1 expression in cumulus GC's is a positive predictor of oocyte maturity, fertilization, embryo development and pregnancy rate in women undergoing IVF [6][7][8][9][10][11]. Our data suggests a corollary to these findings: that a decrease in GREM1 expression in cumulus GC's is specific to women with diminished reproductive potential.…”

Section: Discussionsupporting

confidence: 65%

“…Growth and differentiation factor 9 (GDF9) and its homologues bone morphogenic protein 15 (BMP15, also known as GDF9ß) and BMP6 are currently regarded as the best candidate molecules responsible for oocyte regulation of cumulus GC expansion during ovulation, which is imperative for normal oocyte development in vivo [5]. GDF9 induces cumulus GC gene expression of gremlin 1 (GREM1) [5], a highly-conserved member of the differential screening-selected gene aberrative in neuroblastoma (DAN) family of secreted factors involved in regulating the balance of GDF9 and BMP15 correlated with embryonic development [6].…”

Section: Introductionmentioning

confidence: 99%

“…Increased GREM1 expression in human cumulus GC's has been associated with better blastocyst formation [7,8], good embryo quality and a nonsignificantly improved pregnancy rate [9], and increased female age and good embryo development but decreased serum progesterone on day of hCG in women who received FSH alone but not FSH and LH [10]. The literature reflects considerable between-patient variation for human cumulus GC GREM1 expression [6,10], and given the complexity of the interactions observed and the currently limited knowledge about the function of the cumulus GC genes, it is still difficult to fully explain the biological/causal correlations seen [11].…”

Section: Introductionmentioning

confidence: 99%

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Impaired Gremlin 1 (GREM1) expression in cumulus cells in young women with diminished ovarian reserve (DOR)

Jindal

Greenseid

Berger

et al. 2011

J Assist Reprod Genet

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Purpose A symbiotic relationship between ovarian granulosa cells (GC) and the developing oocyte is critical. Genetic modulations in GC's can lead to reproductive insufficiency, highlighting the role of GC's in reproductive competence. Utilizing gene expression analyses in cumulus GC's, we attempt to enhance our understanding of mechanisms that may contribute to poor reproductive capacity in young women with diminished ovarian reserve (DOR). MethodsWe measured gremlin 1 (GREM1) gene expression in GC's from infertile women <38 years undergoing in vitro fertilization in the context of DOR. Results GREM1, a member of the differential screeningselected gene aberrative in neuroblastoma (DAN) family of genes known for its highly regulated expression pattern during folliculogenesis and a downstream effecter of oocytederived growth and differentiation factor 9, was downregulated 3-fold (−3.08) in women with DOR versus control; down-regulation was confirmed by qRT-PCR (−4.02). Financial Support This investigation was supported by grants from Ferring Pharmaceuticals, Inc (to SJ) and NIH grants 5K12 RR17672 (to LP) and K24 CD41978 (to NS).Capsule Gremlin 1 expression is impaired in cumulus granulosa cells of young women with diminished ovarian reserve (DOR), suggesting a possible mechanism for the ovarian dysfunction associated with DOR. Reprod Genet (2012) 29:159-162 DOI 10.1007 Conclusion This is the first demonstration linking differential expression of Gremlin with etiology of infertility in women.

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impaired Gremlin 1 (GREM1) expression in cumulus cells in young women with diminished ovarian reserve (DOR)

Jindal

Greenseid

Berger

et al. 2011

J Assist Reprod Genet

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“…The granulosa cells of the ovarian follicle support and nurture the oocyte and secrete estrogens which establish a functional bidirectional crosstalk with the oocyte through gap junctions and paracrine factors, and GCs are necessary for normal reproductive function (Langhout et al 1991;Petro et al 2012). Several studies have been published, demonstrating that the gene expression of GCs may differ in relation to the potential development of the embryo (McKenzie et al 2004;Wathlet et al 2011). Heat stress induced the alternation of progesterone production in cumulus cells which are surrounding the bovine oocyte during Fig.…”

Section: Discussionmentioning

confidence: 99%

The effect of heat stress on gene expression, synthesis of steroids, and apoptosis in bovine granulosa cells

Luo

et al. 2016

Cell Stress and Chaperones

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Summer heat stress (HS) is a major contributing factor in low fertility in lactating dairy cows in hot environments. Heat stress inhibits ovarian follicular development leading to diminished reproductive efficiency of dairy cows during summer. Ovarian follicle development is a complex process. During follicle development, granulosa cells (GCs) replicate, secrete hormones, and support the growth of the oocyte. To obtain an overview of the effects of heat stress on GCs, digital gene expression profiling was employed to screen and identify differentially expressed genes (DEGs; false discovery rate (FDR) ≤ 0.001, fold change ≥2) of cultured GCs during heat stress. A total of 1211 DEGs including 175 upregulated and 1036 downregulated ones were identified, of which DEGs can be classified into Gene Ontology (GO) categories and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The results suggested that heat stress triggers a dramatic and complex program of altered gene expression in GCs. We hypothesized that heat stress could induce the apoptosis and dysfunction of GCs. Real-time reverse transcription-polymerase chain reaction (RT-PCR) was used to evaluate the expression of steroidogenic genes (steroidogenic acute regulatory protein (Star), cytochrome P-450 (CYP11A1), CYP19A1, and steroidogenic factor 1 (SF-1)) and apoptosis-related genes (caspase-3, BCL-2, and BAX). Radio immunoassay (RIA) was used to analyze the level of 17β-estradiol (E 2 ) and progesterone (P 4 ). We also assessed the apoptosis of GCs by flow cytometry. Our data suggested that heat stress induced GC apoptosis through the BAX/BCL-2 pathway and reduced the steroidogenic gene messenger RNA (mRNA) expression and E 2 synthesis. These results suggest that the decreased function of GCs may cause ovarian dysfunction and offer an improved understanding of the molecular mechanism responsible for the low fertility in cattle in summer.

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“…In this retrospective study, they selected an 8 gene panel, HAS2, follicle=stimulating hormone receptor (FSHR), solute carrier family 2 member 4 (SLC2A4), activated leukocyte cell adhesion molecule (ALCAM), secreted frizzled-related protein 2 (SFRP2), VCAN, NRP1 and PGR based on prior published studies (McKenzie et al 2004, Gebhardt et al 2011, Wathlet et al 2011, Fragouli et al 2012, Iager et al 2013 to predict the mature oocytes that would lead to live birth. Based on their qRT-PCR results, it was determined that HAS2, FSHR, VCAN and PGR would be the best genes to rank the oocytes.…”

Section: Predictive Modelsmentioning

confidence: 99%

Granulosa cell biomarkers to predict pregnancy in ART: pieces to solve the puzzle

Kordus

LaVoie

2017

Reproduction

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Cumulus and mural granulosa cells of the ovarian follicle surround and interact with the developing oocyte. These follicular cells reflect the oocyte's overall health and may indicate subsequent developmental competence of embryos. Biomarkers of granulosa cells associated with individual oocytes could potentially be used in assisted reproduction to indicate which embryos have the best chance of implanting in the uterus and completing gestation. In this review, we have performed a comprehensive assessment of the recent literature for human cumulus and mural granulosa cell mRNA biomarkers as they relate to pregnancy and live birth. A critical discussion of variables affecting granulosa gene expression profiles for in vitro fertilization patients, including patient demographics and ovarian stimulation regimens, is presented. Although studies with microarray data were evaluated, this synopsis focuses on expressed genes that have been validated by quantitative RT-PCR. Furthermore, we summarize the current published data that support or refute identified granulosa expressed genes as potential biomarkers of embryos that give rise to ongoing pregnancy and live birth. Finally, we review studies that offer predictive models for embryo selection for uterine transfer based on biomarkers that show differential gene expression. Reproduction (2017) 153 R69-R83

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Cumulus cell gene expression predicts better cleavage-stage embryo or blastocyst development and pregnancy for ICSI patients

Abstract: Multivariable models based on CC gene expression can be used to predict embryo development and pregnancy.

Cited by 121 publications

References 34 publications

Impaired Gremlin 1 (GREM1) expression in cumulus cells in young women with diminished ovarian reserve (DOR)

Impaired Gremlin 1 (GREM1) expression in cumulus cells in young women with diminished ovarian reserve (DOR)

The effect of heat stress on gene expression, synthesis of steroids, and apoptosis in bovine granulosa cells

Granulosa cell biomarkers to predict pregnancy in ART: pieces to solve the puzzle

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