1. Developmental Biology

Scientists identify potential new method for diagnosing male infertility

A study has revealed a potential new method to test the capacity of sperm to induce cell fusion, which could be used to diagnose male fertility issues.
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Researchers have discovered a new phenomenon where sperm from mice can induce non-reproductive cells from hamsters to fuse and form a syncytia – a cell with multiple nuclei.

The study, published today in eLife, finds that the degree of this multinucleation is dependent on the fertilising potential of the sperm. With further validation, the findings could be used in the development of new diagnostic tools for male infertility.

According to the World Health Organization, infertility is estimated to affect around 15% of the world’s population. Possible solutions include assisted reproductive techniques, such as in vitro fertilisation (IVF). Previously, the hamster oocyte penetration test was used as a way to quantify the ability of a sperm to fertilise an egg – its fusogenic potential. However, this test is now considered obsolete, so there is no current standardised way to specifically analyse the fusogenic potential of a patient’s sperm.

“In mammals, the fusion of the sperm to the plasma membrane of the egg is mediated by the interaction between two proteins: IZUMO1 on the sperm, and JUNO on the egg, or oocyte,” explains co-author Clari Valansi, a Lab Manager at the Department of Biology, Technion – Israel Institute of Technology, Haifa, Israel.

“In our previous work, we showed that mouse sperm can fuse to a type of connective cell called fibroblasts that have been altered to express JUNO,” adds co-author Nicolas Brukman, a postdoctoral researcher at the Department of Biology, Technion – Israel Institute of Technology. “In this study, we looked to further investigate the mechanisms of mammalian sperm-oocyte fusion.”

The team started by incubating sperm from adult mice with Baby Hamster Kidney (BHK) cells that had been genetically modified to express JUNO. The team were surprised to discover that the sperm cells induced the BHK cells to fuse together and form one cell with multiple nuclei, or a syncytia. This effect was also observed when using the Human Embryonic Kidney cells.

They determined that this multinucleation was dependent on the presence of JUNO. However, this alone was not sufficient to induce the process. Rather, only cells with sperm fused to them formed syncytia, and the level of multinucleation was found to be dependent on the amount of sperm added to the cells. This suggests that the fusion of sperm with JUNO-expressing BHK cells is needed to induce the subsequent multinucleation of the BHK cells.

Next, the team asked whether the multinucleation required JUNO to be present on both fusing BHK cells. They employed a content-mixing experiment in which two populations of cells expressing different fluorescent markers were mixed and exposed to the mouse sperm. There was no BHK-BHK fusion when only one or neither of the cell populations expressed JUNO, suggesting that the sperm-induced multinucleation was indeed dependent on all of the BHK cells expressing JUNO. The team has dubbed this process SPICER (SPerm-Induced CEll-cell fusion Requiring JUNO).

Finally, the team evaluated the potential of SPICER in determining the fusogenic potential of sperm. They incubated mouse sperm in media that prevent capacitation – the process by which sperm acquires its fusogenic capacity – and found that they were subsequently unable to fuse to BHK cells and induce syncytia formation. Furthermore, fully capacitated sperm incubated with an antibody that blocks IZUMO1 also failed to form multinucleated cells. To examine whether the extent of cell-cell fusion relates to the sperm’s fertilising capability, the team assessed the levels of multinucleation in parallel with the performance of the sperm during IVF. They detected a significant positive correlation between syncytia formation and the levels of fertilisation. Taken together, these results suggest that SPICER relies on fully capacitated sperm, as well as the sperm’s fertilising potential, supporting its potential use as a diagnostic tool for male infertility.

The authors call for more research in this area to validate their findings. Future experiments using human sperm would be required to fully realise the potential of SPICER in diagnostic settings.

“We have described a new phenomenon in which sperm cells can induce the fusion of cells expressing JUNO in culture, resembling the viral-like fusion of cells upon infection,” concludes co-author Benjamin Podbilewicz, Professor of Biology in the Department of Biology, Technion – Israel Institute of Technology. “As the extent of multinucleation was correlated with the sperm’s fertilising potential, SPICER could be a step towards the development of a reliable, fast, and simple method for predicting sperm function during the diagnosis of male infertility. It could also be used to predict the success of assisted reproductive techniques such as IVF, or in the agricultural world to evaluate the fertility of stud animals.” Nicolas Brukman, Clari Valansi, and Benjamin Podbilewicz are inventors on a patent application filed by the Technion-Israel Institute of Technology, based on this work.

This study will be included in eLife’s upcoming Special Issue on reproductive health. For more information about the Special Issue, visit https://elifesciences.org/inside-elife/ddab483b/special-issue-call-for-papers-in-reproductive-health.

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    Technion - Israel Institute of Technology


About eLife

eLife transforms research communication to create a future where a diverse, global community of scientists and researchers produces open and trusted results for the benefit of all. Independent, not-for-profit and supported by funders, we improve the way science is practised and shared. In support of our goal, we’ve launched a new publishing model that ends the accept/reject decision after peer review. Instead, papers invited for review will be published as a Reviewed Preprint that contains public peer reviews and an eLife assessment. We also continue to publish research that was accepted after peer review as part of our traditional process. eLife receives financial support and strategic guidance from the Howard Hughes Medical Institute, Knut and Alice Wallenberg Foundation, the Max Planck Society and Wellcome. Learn more at https://elifesciences.org/about.

To read the latest Developmental Biology research in eLife, visit https://elifesciences.org/subjects/developmental-biology.

About Technion - Israel Institute of Technology

Founded in 1912, Technion-Israel Institute of Technology is Israel’s first university and its largest center of applied research. Technion is ranked among the leading technological universities worldwide. A major source of the innovation and brainpower that drives the Israeli economy, Technion is the engine behind Israel’s renown as the iconic “Startup Nation.” Technion people, ideas, and inventions have made, and continue to make tremendous scientific contributions in fields such as medicine, sustainable energy, computer science, water conservation, and nanotechnology. It is one of a handful of technological institutes worldwide with a medical school, facilitating the rapid development of advanced therapies and devices, from the laboratory to the patient's bedside.

Technion’s success is attributed to its unwavering commitment to excellence in education and research. The University is proud of its four Nobel laureates – Aaron Ciechanover, Avram Hershko, Dan Shechtman, and Arieh Warshel. Technion currently ties with MIT in 8th place for the number of Nobel prizewinners this century.

Technion offers degrees in all fields of science and engineering, architecture and town planning, medicine, industrial management, education, and environmental studies. It houses 18 faculties, 60 research centers and institutes, and 10 interdisciplinary research frameworks. There are 14,500 students (10,000 undergraduate and 4,500 graduate) and 580 faculty members. Technion City’s 300-acre campus sits atop Mount Carmel and encompasses 108 main buildings, with additional campuses located in Haifa and Tel Aviv.

In 2011, Technion and Cornell University partnered to establish an applied science and engineering institution in New York City: The Joan and Irwin Jacobs Technion Cornell Institute (JTCI). In 2013, Technion joined with Shantou University to establish the Guangdong Technion-Israel Institute of Technology (GTIT) in China.

To read more, visit : https://www.technion.ac.il/en/home-2/

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