Reproductive cells on demand: Kyoto University researchers illuminate factors driving primordial germ cell development

5 August 2013

Continuing a string of recent achievements, a group of Kyoto University researchers has succeeded in charting the early development of reproductive cells in mice. The team, led by Kyoto University's School of Medicine and Institute for Integrated Cell-Material Sciences (iCeMS) Professor Mitinori Saitou, discovered that three genes are enough to promote epiblast cells into primordial germ cells, precursors of sperm and eggs. One day, these findings may have an impact on fertility treatment.

In reports published in the past two years that have made headlines, the group showed that protein cocktails could make sperm or eggs in a petri dish, from embryonic stem cells and induced pluripotent stem cells (iPS). These reproductive cells were capable of producing healthy, fertile offspring.

"The protein cocktail works well for inducing sperm and eggs from precursor cells, but a bigger question remains," said Saitou, "regarding the factors that drive the change of the cellular state."

This time around, their new study published in Nature focused on specific genes -- known as Blimp1, Prdm14, and Tfap2c -- involved in reshaping the DNA landscape of epiblasts to cause primordial germ cell-like differentiation.

To test the impact of these genes, the group used engineered epiblast-like cells, precursors that emit fluorescent light only if the cells are coaxed into a primordial germ cell-like state. After adding different combinations of the genes into these cells, the researchers monitored which gene permutations caused the cells to light up.

"We found that all three genes together were able to activate a key primordial germ cell program in up to 80% of the cells within a couple of days of their addition," explained Fumio Nakaki, another author of the study. "Prdm14 stood out as the only factor able to induce the differentiation by itself whereas the other factors needed more than one gene to accomplish the same feat, albeit at different efficiencies."

The scientists went on to transplant these coaxed primordial germ cell-like cells into the testes of newborn mice lacking the ability to produce sperm. Within 10 weeks, the transplanted cells were able to restore mature sperm production. Next, sperm taken from these mice were used to fertilize eggs from a healthy female mouse donor in a petri dish, and successful zygotes were transplanted into a surrogate female mouse. After eighteen days, healthy offspring were born, which developed into fertile adults.

"Our results are exciting because they give us more control over regulating reproductive cell development," said Nakaki.

However, because the genes involved in germ cell development in mice may be different from those in humans, the authors caution that more studies are needed before drawing any comparisons between the two. Despite being wary, Saitou is hopeful that their strategy could be put to further use.

"The approach we used in our study to characterize relevant genes involved in reproductive cell development could be applied to other mammals, including humans," said Saitou.

by Peter Gee, public relations URA (university research administrator)

Publication Information

  1. Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
  2. Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin Yoshida, Sakyo-ku, Kyoto 606-8507, Japan.
  3. JST, PRESTO, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
  4. JST, ERATO, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
  5. Institute for Integrated Cell-Material Sciences, Kyoto University, Yoshida-Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan.