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Comparative analysis of different nuclear transfer techniques to prevent the transmission of mitochondrial DNA variants.

Abstract：

:Prevention of mitochondrial DNA (mtDNA) diseases may currently be possible using germline nuclear transfer (NT). However, scientific evidence to compare efficiency of different NT techniques to overcome mtDNA diseases is lacking. Here, we performed four types of NT, including first or second polar body transfer (PB1/2T), maternal spindle transfer (ST) and pronuclear transfer (PNT), using NZB/OlaHsd and B6D2F1 mouse models. Embryo development was assessed following NT, and mtDNA carry-over levels were measured by next generation sequencing (NGS). Moreover, we explored two novel protocols (PB2T-a and PB2T-b) to optimize PB2T using mouse and human oocytes. Chromosomal profiles of NT-generated blastocysts were evaluated using NGS. In mouse, our findings reveal that only PB2T-b successfully leads to blastocysts. There were comparable blastocyst rates among PB1T, PB2T-b, ST and PNT embryos. Furthermore, PB1T and PB2T-b had lower mtDNA carry-over levels than ST and PNT. After extrapolation of novel PB2T-b to human in vitro matured (IVM) oocytes and in vivo matured oocytes with smooth endoplasmic reticulum aggregate (SERa) oocytes, the reconstituted embryos successfully developed to blastocysts at a comparable rate to ICSI controls. PB2T-b embryos generated from IVM oocytes showed a similar euploidy rate to ICSI controls. Nevertheless, our mouse model with non-mutated mtDNAs is different from a mixture of pathogenic and non-pathogenic mtDNAs in a human scenario. Novel PB2T-b requires further optimization to improve blastocyst rates in human. Although more work is required to elucidate efficiency and safety of NT, our study suggests that PBT may have the potential to prevent mtDNA disease transmission.

journal_name

Mol Hum Reprod

journal_title

Molecular human reproduction

authors

Tang M,Guggilla RR,Gansemans Y,Van der Jeught M,Boel A,Popovic M,Stamatiadis P,Ferrer-Buitrago M,Thys V,Van Coster R,Deforce D,De Sutter P,Van Nieuwerburgh F,Heindryckx B

doi

10.1093/molehr/gaz062

subject

Has Abstract

pub_date

2019-12-01 00:00:00

pages

797-810

issue

eissn

1360-9947

issn

1460-2407

pii

5606325

journal_volume

pub_type

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Comparative analysis of different nuclear transfer techniques to prevent the transmission of mitochondrial DNA variants.