Researchers have succeeded in creating a biparental mouse – a mouse born from two male parents – by precisely altering genes involved in genomic imprinting, thereby circumventing a major barrier to mammalian reproduction. However, most of the mice were sick

A stem cell research team has succeeded in engineering a biparental mouse – a mouse with two male parents – using embryonic stem cell technology.
The mouse managed to survive to adulthood, marking a significant breakthrough in reproductive science. Their findings, published January 28, 2025, in the journal Cell Stem Cell, describe how researchers circumvented the long-standing barriers that have hindered same-sex reproduction in mammals by precisely altering key genes involved in the reproductive process.
Scientists have previously tried to create biparental mice, but the embryos only developed to a certain stage and then stopped developing. In this case, the researchers, led by corresponding author Wei Li of the Chinese Academy of Sciences (CAS) in Beijing, focused on targetingEmbedded genes (imprinting genes) – genes that affect gene expression in a variety of ways. “Our work will help overcome many limitations in stem cell research and innovative medicine,” says Lee.
"The characteristics of imprinted genes have led researchers to conclude that they constitute a fundamental barrier to same-sex reproduction in mammals," adds corresponding author Qi Zhao, also from the Chinese Academy of Sciences. "Even when trying to construct biparental or biparental embryos artificially, they do not develop properly and are delayed at some stage in development because of these genes."
Biparental mouse engineering
Previous attempts to create a biparental mouse used ovarian organoids to generate egg cells from male pluripotent stem cells; these egg cells were then fertilized with sperm cells from another male. But when the homologous chromosomes—the chromosomes that separate in meiosis to form egg and sperm cells—originated from the same species, imprinting abnormalities occurred, leading to severe developmental defects.
Imprinted gene alterations in spermatozoa-derived single-chromosomal embryonic stem cells
In this study, 20 key genes involved in imprinting were individually altered using a number of techniques—including frameshift mutations, gene deletions, and regulatory region editing. It was found that not only did these alterations allow the creation of biparental animals that sometimes reached adulthood, but they also resulted in stem cells with more stable pluripotency.
"These findings provide clear evidence that imprinting abnormalities are the main barrier to mammalian same-sex reproduction," explains corresponding author Guan-Zheng Luo of Sun Yat-sen University in Wangzhou. "This approach could significantly improve the developmental outcomes of embryonic stem cells and cloned animals, opening a promising avenue for advancing innovative medicine."
Challenges and future research
The researchers note several limitations that still need to be addressed. First, only 11.8% of the embryos that showed developmental potential led to birth, and not all of the pups that were born survived to adulthood due to developmental defects. Most of those that did reach adulthood exhibited altered growth rates and reduced lifespans. In addition, the adult mice that emerged in the study were dwarfed, although they also showed increased reproductive efficiency.
"Further modifications to imprinted genes may help generate healthy biparental mice that can produce viable gametes, and may even lead to the development of new therapeutic strategies for imprinting-related diseases," explains corresponding author Qi-kun Li of the Chinese Academy of Sciences.
The team plans to continue investigating how changes in imprinted genes might lead to embryos with higher developmental potential. They aim to extend the experimental approaches developed in mice to larger animals, including monkeys. However, the researchers note that this will require considerable time and effort, as the combinations of genes imprinted in monkeys are significantly different from those in mice. Whether the technology will ultimately be used to solve medical problems in humans remains open to debate. It should be noted that the ethical guidelines of the International Organization for Stem Cell Research currently prohibit heritable genome editing for reproductive purposes and the use of gametes derived from human stem cells for reproduction, as they are currently considered unsafe technology.
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