Summary: Researchers have engineered bi-paternal mice—animals derived from two male parents—using embryonic stem cell engineering and targeted edits to imprinting genes. By altering 20 critical imprinted loci, the team overcame major developmental barriers that previously prevented unisexual reproduction in mammals, producing some offspring that survived to adulthood.
Although only 11.8% of manipulated embryos developed to term and many of the survivors displayed growth abnormalities, infertility, and a shortened lifespan, the study demonstrates that imprinting irregularities are a principal obstacle to creating viable same-sex mammalian offspring. The work advances understanding of imprinting’s role in development and offers potential routes for improving stem cell and cloning outcomes, while highlighting important ethical and technical limits to translating this approach to larger animals or humans.
Key Facts:
- Breakthrough technique: Direct modification of 20 imprinting genes enabled production of bi-paternal mice that sometimes reached adulthood.
- Developmental limitations: Only 11.8% of embryos reached birth, and many pups had developmental defects or failed to survive to maturity.
- Research goals: The team plans to improve survival and health outcomes and explore whether similar strategies can be adapted for larger animals.
Source: Cell Press
Lead Summary
A team of stem cell scientists led by Wei Li at the Chinese Academy of Sciences (CAS) in Beijing has reported the generation of adult bi-paternal mice through targeted edits to imprinted genes. Published January 28, 2025 in Cell Stem Cell (Cell Press), the study identifies imprinting defects as the dominant barrier preventing embryos created from same-sex parents from developing to term.
Previous attempts to produce bi-paternal mammals stalled during embryonic development. In earlier work, researchers derived oocytes from male pluripotent stem cells using ovarian organoids and fertilized them with sperm from other males, but embryos with homologous chromosomes from the same sex exhibited severe imprinting abnormalities and failed to develop properly.
To address this, the CAS-led team focused on imprinting genes—genes whose expression depends on parental origin and that regulate development through DNA methylation and other epigenetic mechanisms. The researchers individually modified 20 key imprinted loci using a combination of frameshift mutations, gene deletions, and regulatory-region edits. These changes aimed to reestablish a viable imprinting pattern de novo in embryos derived from two paternal genomes.
The interventions enabled the production of some viable bi-paternal pups and, in rare cases, animals that lived to adulthood. The edited stem cells also displayed improved stability in pluripotency assays, suggesting the approach can improve both embryonic development and stem cell quality.
Co-corresponding authors Qi Zhou (CAS) and Guan‑Zheng Luo (Sun Yat-sen University) emphasize that the study provides strong evidence implicating imprinting defects as the main barrier to unisexual mammalian reproduction. Co-corresponding author Zhi‑Kun Li (CAS) notes that further refinement of imprinting edits may eventually allow the generation of healthier bi-paternal animals able to produce viable gametes and could inform therapeutic strategies targeting imprinting-related diseases.
However, major limitations remain. Only 11.8% of manipulated embryos developed to birth, and many pups experienced developmental defects; several that reached adulthood were sterile and exhibited altered growth and reduced lifespan. While these animals showed increased cloning efficiency, they were not fully healthy or reproductively competent.
The research team plans to refine imprinting modifications to raise developmental success and extend the strategy to larger mammals, including nonhuman primates. They caution that imprinting patterns differ significantly between species, so translating results from mice to monkeys or other animals will require substantial additional work and validation.
Whether this line of research will ever be applied to human reproductive medicine is uncertain. Current international guidelines, such as those from the International Society for Stem Cell Research, prohibit heritable genome editing for reproductive purposes and the use of human stem cell–derived gametes for reproduction because of safety and ethical concerns.
About this genetic engineering and reproduction research news
Author: Kristopher Benke
Source: Cell Press
Contact: Kristopher Benke – Cell Press
Image: The image is credited to Neuroscience News
Original Research: Open access. “Adult bi-paternal offspring generated through direct modification of imprinted genes in mammals” by Wei Li et al., published in Cell Stem Cell (January 28, 2025).
Abstract
Adult bi-paternal offspring generated through direct modification of imprinted genes in mammals
Imprinting abnormalities pose a major challenge for applications using embryonic stem cells, induced pluripotent stem cells, and cloned animals. Because imprinting defects are complex and often stochastic, universal correction methods are lacking. This study targeted imprinting defects directly in embryos from same-sex parents, aiming to create maintainable imprinting patterns de novo in mammalian cells. By introducing frameshift mutations, gene deletions, and regulatory edits at 20 key imprinted loci in bi-paternal mouse embryos—animals that normally show severe, non-viable imprinting defects—the authors achieved development of fully adult offspring, albeit at modest efficiency. These results support the conclusion that imprinting irregularities are a primary barrier to unisexual reproduction in mammals and suggest a strategy to improve outcomes in stem cell and cloning technologies, with implications for regenerative medicine research.