Home LiteratureArticle Details
PMID: 20890283 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Non-invasive imaging of human embryos before embryonic genome activation predicts development to the blastocyst stage.

Nature biotechnology ·Vol. 28 ·No. 10 ·2010-10-00 ·Pages 1115-21

Wong CC, Loewke KE, Bossert NL, Behr B, De Jonge CJ, Baer TM, Reijo Pera RA

Abstract

We report studies of preimplantation human embryo development that correlate time-lapse image analysis and gene expression profiling. By examining a large set of zygotes from in vitro fertilization (IVF), we find that success in progression to the blastocyst stage can be predicted with >93% sensitivity and specificity by measuring three dynamic, noninvasive imaging parameters by day 2 after fertilization, before embryonic genome activation (EGA). These parameters can be reliably monitored by automated image analysis, confirming that successful development follows a set of carefully orchestrated and predictable events. Moreover, we show that imaging phenotypes reflect molecular programs of the embryo and of individual blastomeres. Single-cell gene expression analysis reveals that blastomeres develop cell autonomously, with some cells advancing to EGA and others arresting. These studies indicate that success and failure in human embryo development is largely determined before EGA. Our methods and algorithms may provide an approach for early diagnosis of embryo potential in assisted reproduction.

MeSH Terms
Algorithms Automation Biomarkers/metabolism Blastocyst/metabolism,pathology Cytokinesis/genetics Embryonic Development/genetics Gene Expression Regulation, Developmental Genome, Human/genetics Humans Imaging, Three-Dimensional/methods Mitosis/genetics Models, Genetic Reproducibility of Results Time Factors
Chemicals
Biomarkers
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Wong Connie C
Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, California, USA.
Loewke Kevin E
Bossert Nancy L
Behr Barry
De Jonge Christopher J
Baer Thomas M
Reijo Pera Renee A
References (58)
58 references, click to expand
  1. Time from insemination to first cleavage predicts developmental competence of human preimplantation embryos in vitro.
    Hum Reprod. 2002 Feb;17(2):407-12 PMID: 11821286
  2. Development of the human dispermic embryo.
    Hum Reprod Update. 1999 Sep-Oct;5(5):553-60 PMID: 10582794
  3. The unique transcriptome through day 3 of human preimplantation development.
    Hum Mol Genet. 2004 Jul 15;13(14):1461-70 PMID: 15150160
  4. Relationship between embryo quality and aneuploidies.
    Reprod Biomed Online. 2006 Jan;12(1):77-82 PMID: 16454940
  5. Kinetic markers of human embryo quality using time-lapse recordings of IVF/ICSI-fertilized oocytes.
    Reprod Biomed Online. 2008 Sep;17(3):385-91 PMID: 18765009
  6. Expression profiles of individual human oocytes using microarray technology.
    Reprod Biomed Online. 2004 Mar;8(3):325-37 PMID: 15038899
  7. The human cumulus--oocyte complex gene-expression profile.
    Hum Reprod. 2006 Jul;21(7):1705-19 PMID: 16571642
  8. Vitrification in assisted reproduction: myths, mistakes, disbeliefs and confusion.
    Reprod Biomed Online. 2009;19 Suppl 3:1-7 PMID: 20034418
  9. A genome-wide study of gene activity reveals developmental signaling pathways in the preimplantation mouse embryo.
    Dev Cell. 2004 Jan;6(1):133-44 PMID: 14723853
  10. Preliminary observations on polar body extrusion and pronuclear formation in human oocytes using time-lapse video cinematography.
    Hum Reprod. 1997 Mar;12(3):532-41 PMID: 9130755
  11. Chromosome instability is common in human cleavage-stage embryos.
    Nat Med. 2009 May;15(5):577-83 PMID: 19396175
  12. The first cleavage of the mouse zygote predicts the blastocyst axis.
    Nature. 2005 Mar 17;434(7031):391-5 PMID: 15772664
  13. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes.
    Genome Biol. 2002 Jun 18;3(7):RESEARCH0034 PMID: 12184808
  14. Effect of limited DNA methylation reprogramming in the normal sheep embryo on somatic cell nuclear transfer.
    Biol Reprod. 2004 Jul;71(1):185-93 PMID: 14998909
  15. Towards a single embryo transfer.
    Reprod Biomed Online. 2003 Jun;6(4):470-81 PMID: 12831597
  16. Female subfertility.
    Lancet. 2002 Jul 13;360(9327):151-9 PMID: 12126838
  17. DNA methylation pattern in human zygotes and developing embryos.
    Reproduction. 2004 Dec;128(6):703-8 PMID: 15579587
  18. RNA transcript profiling during zygotic gene activation in the preimplantation mouse embryo.
    Dev Biol. 2005 Jul 1;283(1):40-57 PMID: 15975430
  19. Culture and transfer of viable blastocysts: a feasible proposition for human IVF.
    Hum Reprod. 2000 Dec;15 Suppl 6:9-23 PMID: 11261487
  20. Early embryo cleavage is a strong indicator of embryo quality in human IVF.
    Hum Reprod. 2001 Dec;16(12):2652-7 PMID: 11726590
  21. Evidence that human blastomere cleavage is under unique cell cycle control.
    J Assist Reprod Genet. 2009 Apr;26(4):187-95 PMID: 19288185
  22. Reproductive biology: delivering spermatozoan RNA to the oocyte.
    Nature. 2004 May 13;429(6988):154 PMID: 15141202
  23. Expression of genes involved in early cell fate decisions in human embryos and their regulation by growth factors.
    Reproduction. 2008 May;135(5):635-47 PMID: 18411410
  24. A novel and critical role for Oct4 as a regulator of the maternal-embryonic transition.
    PLoS One. 2008;3(12):e4109 PMID: 19129941
  25. Automated cell lineage tracing in Caenorhabditis elegans.
    Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2707-12 PMID: 16477039
  26. Zygotic and embryonic gene expression in cow: a review of timing and mechanisms of early gene expression as compared with other species.
    Zygote. 2000 Feb;8(1):87-96 PMID: 10840878
  27. Imprinting disorders and assisted reproductive technology.
    Fertil Steril. 2009 Feb;91(2):305-15 PMID: 19201275
  28. qBase relative quantification framework and software for management and automated analysis of real-time quantitative PCR data.
    Genome Biol. 2007;8(2):R19 PMID: 17291332
  29. Epigenetics and assisted reproductive technology: a call for investigation.
    Am J Hum Genet. 2004 Apr;74(4):599-609 PMID: 14991528
  30. Preimplantation embryo programming: transcription, epigenetics, and culture environment.
    Reproduction. 2008 Feb;135(2):141-50 PMID: 18239045
  31. The role of centrosomes in fertilization, cell division and establishment of asymmetry during embryo development.
    Semin Cell Dev Biol. 2010 Apr;21(2):174-84 PMID: 20083214
  32. Dynamic multiple-target tracing to probe spatiotemporal cartography of cell membranes.
    Nat Methods. 2008 Aug;5(8):687-94 PMID: 18604216
  33. Computational prediction of neural progenitor cell fates.
    Nat Methods. 2010 Mar;7(3):213-8 PMID: 20139969
  34. Conception to ongoing pregnancy: the 'black box' of early pregnancy loss.
    Hum Reprod Update. 2002 Jul-Aug;8(4):333-43 PMID: 12206468
  35. Mechanisms of maternal mRNA regulation: implications for mammalian early embryonic development.
    Front Biosci. 2007 May 01;12:3713-26 PMID: 17485333
  36. Distinctive chromatin in human sperm packages genes for embryo development.
    Nature. 2009 Jul 23;460(7254):473-8 PMID: 19525931
  37. Significance of morphological attributes of the early embryo.
    Reprod Biomed Online. 2005 May;10(5):669-81 PMID: 15949228
  38. Human gene expression first occurs between the four- and eight-cell stages of preimplantation development.
    Nature. 1988 Mar 31;332(6163):459-61 PMID: 3352746
  39. Single blastocyst transfer: a prospective randomized trial.
    Fertil Steril. 2004 Mar;81(3):551-5 PMID: 15037401
  40. Assisted reproduction: the epigenetic perspective.
    Hum Reprod Update. 2005 Sep-Oct;11(5):473-82 PMID: 15994847
  41. Does severe teratozoospermia affect blastocyst formation, live birth rate, and other clinical outcome parameters in ICSI cycles?
    Fertil Steril. 2010 Mar 1;93(4):1097-103 PMID: 19200957
  42. Reduction in exposure of human embryos outside the incubator enhances embryo quality and blastulation rate.
    Reprod Biomed Online. 2010 Apr;20(4):510-5 PMID: 20129824
  43. Comparison of blastocyst transfer with day 3 embryo transfer in similar patient populations.
    Fertil Steril. 2000 Jan;73(1):126-9 PMID: 10632426
  44. Developmental expression of specific genes detected in high-quality cDNA libraries from single human preimplantation embryos.
    Gene. 1999 Sep 17;237(2):373-83 PMID: 10521661
  45. The transcriptome of human oocytes.
    Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14027-32 PMID: 16968779
  46. High rates of embryonic loss, yet high incidence of multiple births in human ART: is this paradoxical?
    Theriogenology. 2002 Jan 1;57(1):87-96 PMID: 11775983
  47. Blastocyst score affects implantation and pregnancy outcome: towards a single blastocyst transfer.
    Fertil Steril. 2000 Jun;73(6):1155-8 PMID: 10856474
  48. Origin and ploidy of multipronuclear zygotes.
    Reprod Fertil Dev. 1999;11(4-5):273-9 PMID: 10898292
  49. Patterning of the embryo: the first spatial decisions in the life of a mouse.
    Development. 2002 Feb;129(4):815-29 PMID: 11861466
  50. Pronuclear stage cryopreservation after intracytoplasmic sperm injection and conventional IVF: implications for timing of the freeze.
    Fertil Steril. 1999 Dec;72(6):1049-54 PMID: 10593380
  51. Significantly enhanced pregnancy rates per cycle through cryopreservation and thaw of pronuclear stage oocytes.
    Fertil Steril. 1993 Jun;59(6):1202-7 PMID: 8495766
  52. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.
    Methods. 2001 Dec;25(4):402-8 PMID: 11846609
  53. Time-course of oocyte activation, pronucleus formation and cleavage in human oocytes fertilized by intracytoplasmic sperm injection.
    Hum Reprod. 1994 Sep;9(9):1743-8 PMID: 7836530
  54. Blastocyst development after vitrification of multipronuclear zygotes using the Flexipet denuding pipette.
    Reprod Biomed Online. 2002 Mar-Apr;4(2):146-50 PMID: 12470577
  55. The first cell-fate decisions in the mouse embryo: destiny is a matter of both chance and choice.
    Curr Opin Genet Dev. 2006 Aug;16(4):406-12 PMID: 16806896
  56. Embryology: does prepatterning occur in the mouse egg?
    Nature. 2006 Jul 13;442(7099):E3-4; discussion E4 PMID: 16837972
  57. In vitro development and implantation rates of fresh and cryopreserved sibling zygotes.
    Obstet Gynecol. 1995 Jun;85(6):999-1002 PMID: 7770273
  58. Robust single-particle tracking in live-cell time-lapse sequences.
    Nat Methods. 2008 Aug;5(8):695-702 PMID: 18641657
Article Info
Journal
Nature biotechnology
Abbr.
Nat Biotechnol
ISSN
1546-1696
DOI
10.1038/nbt.1686
Published
2010-10-00
Epub
2010-00-03
Pages
1115-21
Language
English
Region
United States
NLM ID
9604648
Subset
IM
Corrections
CommentIn
PMID: 20944588
External Links
PubMed source DOI: 10.1038/nbt.1686 View journal details
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