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The origin and possible mechanism of embryonic cell-free DNA release in spent embryo culture media: a review

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Abstract

The presence of cell-free DNA in spent embryo culture media (SECM) has unveiled its possible utilization for embryonic ploidy determination, opening new frontiers for the development of a non-invasive pre-implantation genetic screening technique. While a growing number of studies have shown a high concordance between genetic screening using cell-free DNA (cfDNA) and trophectoderm (TE), the mechanism pertaining to the release of cfDNA in SECM is largely unknown. This review aims to evaluate research evidence on the origin and possible mechanisms for the liberations of embryonic DNA in SECM, including findings on the self-correction abilities of embryos which might contribute to the presence of cfDNA. Several databases including EMBASE, PUBMED, and SCOPUS were used to retrieve original articles, reviews, and opinion papers. The keywords used for the search were related to the origins and release mechanism of cfDNA. cfDNA in SECM originates from embryonic cells and, at some levels, non-embryonic cells such as maternal DNA and exogenous foreign DNA. The apoptotic pathway has been demonstrated to eliminate aneuploid cells in developing mosaic embryos which might culminate to the release of cfDNA in SECM. Nonetheless, there is a recognized need for exploring other pathways such as cross-talk molecules called extracellular vesicles (EVs) made of small, round bi-layer membranes. During in vitro development, embryos physiologically and actively expel EVs containing not only protein and microRNA but also embryonic DNA, hence, potentially releasing cfDNA of embryonic origin into SECM through EVs.

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Abbreviations

cfDNA :

cell-free DNA

Evs :

extracellular vesicle(s)

HSA :

human serum albumin

ICM :

inner cell mass

ICSI :

intra-cytoplasmic sperm injection

IVF :

in vitro fertilization

niPGT-A :

non-invasive pre-implantation genetic testing for aneuploidy

NGS :

next-generation sequencing

PGD :

pre-implantation genetic diagnosis

PGS :

pre-implantation genetic screening

PGT-A :

pre-implantation genetic testing for aneuploidy

PGT-M :

pre-implantation genetic testing for monogenic disorders

PGT-SR :

pre-implantation genetic testing for chromosomal structural rearrangement

qPCR :

quantitative polymerase chain reaction

SAC :

spindle assembly checkpoint

SECM :

spent embryo culture media

TE :

trophectoderm cells

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Acknowledgements

GB Danardono has provided valuable assistance in helping the authors draw the image.

Funding

The authors received PUTI Grant from the Universitas Indonesia (NKB-1293/UN2.RST/HKP.05.00/2022).

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Authors and Affiliations

  1. Doctoral Program in Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

    Nining Handayani

  2. IRSI Research and Training Centre, Jakarta, Indonesia

    Nining Handayani, Arief Boediono, Batara Sirait, Ivan Sini & Arie A Polim

  3. Indonesia International Institute for Life Sciences, Jakarta, Indonesia

    Daniel Aubry

  4. Morula IVF Jakarta Clinic, Jakarta, Indonesia

    Arief Boediono, Batara Sirait, Ivan Sini & Arie A Polim

  5. Department of Anatomy, Physiology and Pharmacology, IPB University, Bogor, Indonesia

    Arief Boediono

  6. Faculty of Medicine, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Universitas Indonesia, Jakarta, Indonesia

    Budi Wiweko

  7. Department of Obstetrics and Gynaecology, Faculty of Medicine Universitas Kristen Indonesia, Jakarta, Indonesia

    Batara Sirait

  8. Department of Obstetrics and Gynecology, School of Medicine and Health Sciences, Atmajaya Catholic University of Indonesia, Jakarta, Indonesia

    Arie A Polim

  9. Cellular and Molecular Mechanisms in Biological System (CEMBIOS) Research Group, Faculty of Mathematics and Natural Sciences, Department of Biology, Universitas Indonesia, Kampus FMIPA, Depok, UI, 16424, Indonesia

    Astari Dwiranti & Anom Bowolaksono

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All authors contributed to the study’s conception. Database searching and journal selection were performed by Nining Handayani. Anom Bowolaksono and Daniel Abidin Aubry checked scientific content accuracy. The first draft of the manuscript was written by Nining Handayani, and all authors commented on previous versions of the manuscript. All authors have read and approved the final manuscript.

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Handayani, N., Aubry, D., Boediono, A. et al. The origin and possible mechanism of embryonic cell-free DNA release in spent embryo culture media: a review. J Assist Reprod Genet 40, 1231–1242 (2023). https://doi.org/10.1007/s10815-023-02813-z

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