Artificial mouse sperm from stem cells

“Fertility experts are hailing a mouse study in which working sperm cells were created from embryonic stem cells in mice as ‘hugely exciting’,” reports the BBC. Other news sources have suggested that these results offer hope to men with infertility.

This story was covered by a number of papers and is based on a report published in the journal Cell . Using stem cells from mouse embryos, researchers were able to make the very early progenitors of the cells that go on to form sperm. When these cells were transplanted back into male mice they formed sperm, and this sperm could be used to produce healthy, fertile mice. The researchers also achieved similar results with cells that they “forced” to become stem cells, but some of the offspring born from these sperm died prematurely.

These results will allow further research into how the cells that produce sperm develop, an area that has been difficult to investigate due to the difficulty of growing these cells in the laboratory. Before these techniques could treat infertility in humans, much more research in animals is needed to perfect them and ensure that they are safe. There will also need to be a debate about any ethical considerations.

Where did the story come from?

The study was carried out by researchers from Kyoto University in Japan. Funding was provided by the Ministry of Education, Culture, Sports, Science and Technology of Japan, JST-CREST, the Takeda Science Foundation and the Uehara Memorial Foundation. The study was published in the peer-reviewed scientific journal Cell .

Generally, the story was well-reported. The BBC in particular used a good headline that immediately makes clear that the study was in mice. Many of the papers included headlines or straplines extrapolating the findings to human fertility. It should be noted that the application of this finding to humans will require time, further research and extensive discussion about the ethical considerations.

What kind of research was this?

This was a laboratory and animal study investigating whether mouse stem cells could be made to develop into the very early precursors of the cells that make sperm in the laboratory, and whether these cells could go on to produce healthy, fully functional sperm if implanted into male mice.

Animal studies are the only way that techniques such as this can be developed and tested, as it would not be ethnical to carry out this type of early research in humans.

What did the research involve?

The researchers extracted male embryonic stem cells from mouse embryos. Embryonic stem cells are a type of cell that have the ability to develop (differentiate) into any of the specialised cell types that make up the body. The researchers tried to develop conditions that would cause the embryonic stem cells to develop into a particular type of cell, called “primordial germ cell-like cells”. Primordial germ cells go on to form germ cells, which then produce eggs or sperm (also called gametes). The researchers monitored which genes were active and which genes were being switched off during the development process. They aimed to emulate what happens normally in the embryo, and to identify genes that are specifically switched on in these primordial germ cell-like cells, which would allow their identification in the laboratory.

The researchers investigated whether the primordial germ cell-like cells they created went on to form sperm in mice. They transplanted the primordial germ cell-like cells into the testes of mice that lacked their own germ cells. These cells were then allowed to develop, and sperm was taken from the mice in which this was successful and used to fertilise oocytes (eggs). The embryos produced were transferred into female mice and the development of the foetuses was monitored. After birth, the researchers investigated whether the offspring were themselves fertile and healthy.

The researchers then tried to repeat their findings using fully developed mouse cells that had been “induced” to become stem cells in the laboratory (called induced pluripotent stem cells). The cells are forced to express specific genes that allow them to act like stem cells.

What were the basic results?

The researchers developed a method of producing primordial germ cell-like cells from embryonic stem cells. These primordial germ cell-like cells had similar profiles of gene activity to primordial germ cells produced in a normally developing embryo. The researchers also identified certain characteristics of these cells that would allow this cell type to be identified in the laboratory.

When these cells were transplanted into the testes of mice lacking their own germ cells, sperm was produced in three out of six cases (50%). The sperm that was produced was used to fertilise mouse eggs in the laboratory, and the resulting embryos were transferred to female mice. Healthy and fertile female and male offspring were produced. This showed that the primordial germ cell-like cells produced in the laboratory from embryonic stem cells can develop into fully functioning germs cells, which produce functional sperm when transplanted back into male mice.

The researchers then tried to repeat their findings using induced pluripotent stem cells. They used three types of induced pluripotent stem cells. One of these three types behaved in a similar manner to embryonic stem cells, and once transplanted into the testes of mice lacking germ cells resulted in sperm formation in three out of 18 cases (17%). Fertile offspring were produced, although some of the offspring died prematurely.

How did the researchers interpret the results?

The researchers concluded that they had managed to generate primordial germ cell-like cells from both embryonic and induced pluripotent stem cells that have a similar gene activation profile and can function in a similar manner to primordial germ cells derived from embryos.

Conclusion

This was a well-performed study, which used mouse stem cells to produce the early cells that eventually go on to produce sperm in the laboratory. These cells went on to produce sperm when transplanted back into mice, and the sperm went on to produce healthy, fertile offspring.

The techniques described represent a major advance as they will allow researchers to explore how these early progenitor cells develop, as the technique can generate a relatively large number of these cells. To date, scientific knowledge of this process has been limited as there are not many of these cells in each embryo and they are difficult to grow in the laboratory.

Several news sources have suggested that this study offers hope to men with infertility. Although these techniques may one day be applicable to humans, it is important to remember that so far they have only been performed in mice. As the authors note, human embryonic stem cells have substantially different properties from mouse embryonic stem cells. Also, it would not be possible to obtain these cells from adult men with infertility. Therefore, the technique would have to be perfected for use with other forms of stem cells, such as the induced stem cells derived from adult cells.

Before any application of these findings could be considered in humans, much more research in animals is needed to ensure that the technique is sufficiently safe and generates full healthy offspring. There will also need to be a debate about how ethical the use of such a technique is.