Autologous bone marrow mesenchymal stem cell mitochondrial transplantation in recurrent assisted reproductive...

Mitochondrial dysfunction contributes to poor embryo quality and recurrent assisted reproductive technology (ART) failure. Mitochondrial transplantation (MIT), which involves supplementing oocytes with exogenous mitochondria, has been proposed as a novel strategy to improve ART outcomes. However, both its clinical efficacy and safety remain unclear.

In this single-center trial, 151 patients with a history of ≥ 2 failed ART cycles provided 1178 metaphase II (MII) oocytes. Sibling oocytes were randomized 1:1 to receive autologous bone marrow mesenchymal stem cells (BMSCs) mitochondria co-injection during intracytoplasmic sperm injection (ICSI) or standard ICSI. The primary outcome was the rate of day-3 good-quality embryos.

MIT significantly accelerated early embryonic cleavage at the 3-cell stage and 5-cell stage, but this morphokinetic alteration did not translate into improvements in good-quality embryo rate, clinical pregnancy rate, or live birth rate. Long-term follow-up of 23 live births revealed no adverse effects, with all offspring exhibiting normal growth and development. Exploratory analysis revealed that oocytes yielding ≥ 70% transferable embryos after MIT harbored an elevated higher burden of medium frequency (0.05-0.5) mtDNA point mutations.

While autologous BMSCs-MIT transiently alters early cleavage kinetics, it does not demonstrate a clinical advantage in unselected patients with recurrent ART failure. Nevertheless, its observed safety profile and the identification of mtDNA mutation burden as a potential predictive biomarker provide a foundation for shifting future MIT research from a universal approach toward precision application in molecularly stratified populations. Trial registration ClinicalTrials.gov registration: NCT03639506.