This image shows a bipaternal mouse pup (born to two fathers). [Leyun Wang]
This image shows a bipaternal mouse pup (born to two fathers). [Leyun Wang]

Using embryonic stem cells and gene editing, healthy mice have been bred from two mothers for the first time. The bimaternal mice not only lived into adulthood, they successfully reproduced with male mice to produce healthy offspring. Mice were also produced from two fathers, but, did not live past a few days.

The work was published recently in the journal Cell Stem Cell in a paper titled, “Generation of Bimaternal and Bipaternal Mice from Hypomethylated Haploid ESCs with Imprinting Region Deletions”.

Co-senior author Qi Zhou, Ph.D. professor at the State Key Laboratory of Stem Cell and Reproductive Biology at the Chinese Academy of Sciences in Beijing, China says, “We were interested in the question of why mammals can only undergo sexual reproduction. We have made several findings in the past by combining reproduction and regeneration, so we tried to find out whether more normal mice with two female parents, or even mice with two male parents, could be produced using haploid embryonic stem cells with gene deletions.”  

In mammals, because certain maternal or paternal genes are shut off through genomic imprinting, offspring that don't receive genetic material from both a mother and a father are likely to be nonviable or have developmental abnormalities.

The research team from the Chinese Academy of Sciences used haploid embryonic stem cells (ESCs), which contain half the normal number of chromosomes and DNA from only one parent and which the researchers believe were the key to their success. The authors write that “cultured parthenogenetic and androgenetic haploid embryonic stem cells (haESCs) display DNA hypomethylation resembling that of primordial germ cells.” Co-senior author Baoyang Hu, M.D., Ph.D., adds, “We found in this study that haploid ESCs were more similar to primordial germ cells, the precursors of eggs and sperm. The genomic imprinting that's found in gametes was 'erased’.”

In this work, the mice were created by deleting three imprinting regions of the genome from haploid ESCs containing a female parent's DNA and injecting them into eggs from another female mouse. Using this method, the team produced 29 live mice from 210 embryos.

Wei Li, Ph.D., a co-senior author on the study, notes that there are still obstacles to using these methods in other mammals. For example, there is a need to identify problematic imprinted genes that are unique to each species and ongoing concerns for the offspring that don't survive or that experience severe abnormalities. They do hope, however, to explore these techniques in other research animals in the future.

This study adds to the understanding of what makes it so challenging for animals of the same sex to produce offspring and suggests that some of these barriers can be overcome using stem cells and targeted gene editing. “This research shows us what's possible,” Dr. Li says. “We saw that the defects in bimaternal mice can be eliminated and that bipaternal reproduction barriers in mammals can also be crossed through imprinting modification. We also revealed some of the most important imprinted regions that hinder the development of mice with same-sex parents, which are also interesting for studying genomic imprinting and animal cloning.” 

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