World first: Mouse stem cells used to make sperm-like cells which produce fertile offspring

Researchers have reported coaxing mouse embryonic stem cells into sperm-like cells which were then used to create fertile offspring. The achievement represents the first time stem cells have successfully been made to reproduce meiosis (cell division that creates germ cells) in the lab. The authors, who describe their technique in Cell Stem Cell, say it could hold “tremendous promise” for treating male infertility in humans.

 

Dr. Kyle Orwig, Professor of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine (webpage):

Expertise: biology of male germline stem cells; regenerative medicine; fertility and infertility; germline development.

“This is an important achievement. The important thing is that they have demonstrated the concept in mice, validated by the production of viable offspring.  Wow!  Only time will tell if this method will work in human cells. Several excellent labs have tried to achieve the result described in this study, most with limited success.  In that regard, this is a landmark report.  However, as with all important scientific advances, it is essential that the results be replicated and confirmed in other laboratories.

“The mice the authors created using embryonic stem cell (ESC) derived cells produce fertile offspring, and they suggest their results could facilitate potential treatments for male infertility. For clinical application, there maybe ethical barriers to treating infertility with ESC-derived cells related to the requirement to use embryos and the fact that the ESCs would not be obtained from the person being treated, so would not enable him to have a genetically related child.

“However,  in principle the same results might be achieved with induced pluripotent stem cells (iPSCs ), which would circumvent most of the ethical concerns.

“Someday and under some circumstances, germline gene therapy might gain acceptance.  If that occurs, iPSCs (not ESCs) could be an outstanding vehicle for correcting infertility-causing genetic defects before differentiation to germ-like cells. It is important to note that infertility is not always due to genetic factors.  For example, sometimes infertility is cause by the toxic effects of chemotherapy or radiation for cancer or other conditions.”

 

Dr. Vittorio Sebastiano, Assistant Professor, Department of Obstetrics and Gynecology, Stanford School of Medicine (webpage):

Expertise: biology of germ cells and pluripotent stem cells; early cell fate decisions in human embryos.

“This study is certainly a milestone in the field. While in vitro derivation of germ cells capable of meiosis had already been proven to some extent, the work of this group surpasses previous attempts, especially considering that the cells were capable of giving rise to viable embryos that could develop into mouse pups. This “functional” test represents the gold standard and until now no-one had been able to show this using an in vitro-only approach.

“The application of this technique to human cells may not, however, be as easy. So far only two groups have shown to be able to generate germ-like cells from human pluripotent cells but there’s no definitive evidence that those cells can progress and mature further. The gene expression profile of human germ cells is similar but still different from that of mouse germ cells. In principle the technique could work in human cells but it may require a few more years to achieve similar results

“The technique described in this paper could potentially be adapted as an infertility treatment if induced pluripotent stem cells (iPSCs) could be generated from infertile men, differentiated into germ cells and further matured by combining them with cells derived from testicular biopsies. Although this approach is not in principle different from being able to generate any other “dysfunctional” organ from patient-derived iPSCs, the fact that we are not simply restoring the functionality but potentially creating cells that could be used to generate embryos raises an endless number of ethical questions and concerns that we have not yet fully discussed. The reason is very simple: whatever alteration we may cause during the process of reprogramming or differentiation of the cells will be passed on to the following generations, and we cannot predict how this could impact the life of the babies that would be conceived using this technique. It is a fascinating topic of discussion.”

 

Dr. Peter Donovan, Professor, Sue and Bill Gross Stem Cell Research Center, University of California, Irvine (webpage):

Expertise: molecular genetics of germ cell and stem cell development.

“This paper reports a significant advance in understanding sperm development and production. Using mouse embryonic stem cells the team was able to first make so-called primordial germ cells: cells that form in the embryo and that will eventually give rise to sperm. They were then able to coax the cells to develop further to make cells like spermatids; not fully mature sperm that can actually swim, but close. The team was then able to introduce these spermatid-like cells into mouse eggs using injection techniques used routinely in in vitro fertilization clinics and generate live mice.

“Of course the next exciting step would be to accomplish the same feat with human cells.  But other studies, which demonstrate that some of the gene pathways required for making human primordial germ cells are different than those required in mice, provide a note of caution. So there might be some things to be discovered before this technology can be translated into humans.

“There are many ethical issues to be considered if this technology was developed in humans. How can we tell if spermatids made in a laboratory are really of the same high quality as those made and tested by natural selection in the testis? How do we know that spermatids made in the lab have not acquired mutations to DNA? Science may well answer these questions in time.

“Making spermatids in a dish from human embryonic stem cells could have important repercussions.  It would allow scientist to continue to understand how our species reproduces, and also offers tantalizing possibilities that might one day be used in treating patients with infertility.  If this technique for making spermatids also works in human induced pluripotent stem cells then it would conceivably be possible to make stem cells from infertile patients, correct a genetic defect in the stem cells and then make spermatids to fertilize the egg. Problem solved.

“In addition, these advances could also conceivably help us understand why certain individuals develop testicular cancer, why older men are more likely to pass on mutations to their offspring and perhaps why certain men become infertile in the first place. The next step will be to see if we want to take the plunge and see if we can make spermatids learn to swim!”

 

Dr. Terry Hassold, Professor, School of Molecular Biosciences, Washington State University (webpage):

Expertise: Chromosome abnormalities in pregnancy; meiotic recombination.

“This has been the black box of these kind of studies: no one has been able to push cells through meiosis and get a functional gamete out of the other end. Most of us who work in the field think that it is too complicated. Importantly, these results need to be replicated in another laboratory, but there’s no question this is a significant advance if they have taken a cell that is not a germ cell and have got progeny out of the other end. 

“The crucial test is whether or not this technique does reliably give rise to genetically normal progeny. The authors do a little bit of work which suggests the progeny are genetically and epigenetically balanced, but there now has to be much more careful characterization, particularly with respect to what’s going on with meiosis – are they getting the right number of chromosomes, and is the chromosome content normal? The bottom line is that this is meiosis lite.

“There’s no question that the technique needs to be improved further, but if we can build on this as a technique that is doable in the laboratory, it really is going to change the way we think about cases of infertility that are currently unable to be treated by IVF. The crucial question is whether someone else going to be able to replicate the study, and if that is the case then it really will revolutionize assisted reproduction as we know it. All the IVF clinics would be likely to hop on it, although in my opinion that would be very premature.”

 

Declared interests (see GENeS register of interests policy):

Dr. Vittorio Sebastiano: “I am trying to develop protocols of derivation of fully functional germ cells from human pluripotent stem cells. I am currently working on a fast, robust and efficient protocol capable to induce primordial germ cells from patients-derived iPSCs. Once created, the next step will be to further mature the germ cells generated and derive meiotic competent cells from them. So my research is trying to achieve the very “end-product”, with the goal to treat patients that are infertile due to a variety of different reasons.”

No further interests declared

 

Reference:

Complete Meiosis from Embryonic Stem Cell-Derived Germ Cells In Vitro‘ by Zhou et al, published in Cell Stem Cell on Thursday 25 February, 2016.

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