Maternal spindle transfer overcomes embryo developmental arrest caused by ooplasmic defects in mice.

Jesús González,Dagan Wells,Gloria Calderón,Nuno Costa-Borges,Ivette Vanrell,Rosa Balmaseda,Klaus Rink,Maria Garcia-Jiménez,Enric Mestres,Katharina Spath,Anna Serafín,Irene Miguel-Escalada

doi:10.7554/elife.48591

Abstract

The developmental potential of early embryos is mainly dictated by the quality of the oocyte. Here, we explore the utility of the maternal spindle transfer (MST) technique as a reproductive approach to enhance oocyte developmental competence. Our proof-of-concept experiments show that replacement of the entire cytoplasm of oocytes from a sensitive mouse strain overcomes massive embryo developmental arrest characteristic of non-manipulated oocytes. Genetic analysis confirmed minimal carryover of mtDNA following MST. Resulting mice showed low heteroplasmy levels in multiple organs at adult age, normal histology and fertility. Mice were followed for five generations (F5), revealing that heteroplasmy was reduced in F2 mice and was undetectable in the subsequent generations. This pre-clinical model demonstrates the high efficiency and potential of the MST technique, not only to prevent the transmission of mtDNA mutations, but also as a new potential treatment for patients with certain forms of infertility refractory to current clinical strategies.

Highlights

Infertility disorders are a growing problem that affects millions of couples worldwide (WHO, 2017)
The results suggest that while some mitochondria remain associated with the meiotic spindle, and are unavoidably transferred to the recipient cytoplast, the vast majority of these organelles do not persist into later developmental stages, with most being expelled into the second polar body at the completion of meiosis II
This proof of concept study provides insights into the feasibility of this technique as a potential new reproductive approach to overcome infertility problems characterized by repeated in vitro embryo development arrest caused by cytoplasmic deficiencies in the oocyte

Summary

Introduction

Infertility disorders are a growing problem that affects millions of couples worldwide (WHO, 2017). The use of donated oocytes is effective at significantly improving the chances of successful IVF treatment, the resultant children are not genetically related to the intended-mothers. It is desirable to develop new reproductive strategies that can allow the treatment of these patients with genetically related oocytes. Poor quality oocytes fail to fertilize or produce embryos that arrest during the first stages of development (Hardy et al, 2001; Meskhi and Seif, 2006; Pellicer et al, 1995) either due to nuclear or cytoplasmic defects (Conti and Franciosi, 2018; Eppig, 1996; Liu and Keefe, 2004). Accumulated evidence suggests that aberrant meiosis or early developmental failure is caused mainly by deficiencies in the oocyte cytoplasmic machinery (Hoffmann et al, 2012; Liu et al, 2003; Liu et al, 1999; Liu et al, 2000; Liu and Keefe, 2007; Reader et al, 2017), which contains a vast diversity of critical

Objectives

Methods

Results

Conclusion