In a groundbreaking development in stem cell engineering, a team of scientists has successfully created a bi-paternal mouse—one with two male parents—that survived to adulthood. The study, published on January 28, 2025, in Cell Stem Cell, details how researchers overcame significant biological barriers to unisexual reproduction in mammals by modifying key imprinting genes.
Overcoming Barriers to Unisexual Reproduction using Stem Cell Engineering
Previous attempts to produce bi-paternal mice had been largely unsuccessful, with embryos failing to develop beyond a particular stage. The team, led by Wei Li of the Chinese Academy of Sciences (CAS) in Beijing, focused on imprinting genes, which regulate gene expression and play a crucial role in reproduction. By modifying these genes, the researchers created bi-paternal embryos that, for the first time, successfully developed into adult mice using Stem Cell Engineering.
“The unique characteristics of imprinting genes have led scientists to believe that they are a fundamental barrier to unisexual reproduction in mammals,” said co-corresponding author Qi Zhou, also of CAS. “Even when constructing bi-maternal or bi-paternal embryos artificially, they fail to develop properly and stall at some point during development due to these genes.”
Gene Editing and Developmental Challenges
The study modified 20 key imprinting genes using frameshift mutations, gene deletions, and regulatory region edits. These genetic changes allowed for the successful creation of bi-paternal mice and improved the stability of embryonic stem cells.
However, significant challenges remain. Only 11.8% of the viable embryos developed until birth; many had developmental abnormalities, shortened lifespans, or failed to reach adulthood. The mice that survived were also sterile, though they exhibited improved cloning efficiency.
“These findings provide strong evidence that imprinting abnormalities are the main barrier to mammalian unisexual reproduction,” said co-corresponding author Guan-Zheng Luo of Sun Yat-sen University in Guangzhou. “This approach can significantly improve the developmental outcomes of embryonic stem cells and cloned animals, paving a promising path for advancing regenerative medicine.”
Future Implications and Ethical Considerations
While the study marks a significant step forward in reproductive biology, the researchers acknowledge that further modifications are needed to improve survival rates and address sterility. The team plans to expand their research to larger animals, including monkeys, though they note that imprinting gene combinations differ significantly between species, making the process more complex.
Despite the scientific progress, the application of this technology in humans remains uncertain. Current ethical guidelines set by the International Society for Stem Cell Research prohibit heritable genome editing for reproductive purposes and human stem cell-derived gametes for reproduction due to safety concerns.
For now, the research offers valuable insights into the genetic mechanisms of reproduction and could have future applications in regenerative medicine and the treatment of imprinting-related diseases. However, significant scientific and ethical hurdles remain before such technology can be considered beyond experimental use.
Reference: Zhi-kun Li, Li-bin Wang, Le-yun Wang, Xue-han Sun, Ze-hui Ren, Si-nan Ma, Yu-long Zhao, Chao Liu, Gui-hai Feng, Tao Liu, Tian-shi Pan, Qing-tong Shan, Kai Xu, Guan-zheng Luo, Qi Zhou, Wei Li. Adult bi-paternal offspring generated through direct modification of imprinted genes in mammals. Cell Stem Cell, 2025.
