Building a new mouse, one stem cell at a time

Science is full of acronyms. There are days where it feels like you need a decoder ring just to understand a simple sentence. A recent study found that between 1950 and 2019 researchers used more than 1.1 million unique acronyms in scientific papers. There’s even an acronym for three letter acronyms. It’s TLAs. Which of course has one more letter than the thing it stands for.

I only mention this because I just learned a new acronym, but this one could help change the way we are able to study causes of infertility. The acronym is IVG or in vitro gametogenesis and it could enable scientists to create both sperm and egg, from stem cells, and grow them in the lab. And now scientists in Japan have done just that and allowed these fertilized eggs to then develop into mice.

The study, published in the journal Science, was led by Dr. Katsuhiko Hayashi of Kyushu University in Japan. Dr. Hayashi is something of a pioneer in the field of IVG. In the past his team were the first to produce both mouse sperm, and mouse eggs from stem cells. But they ran into a big obstacle when they tried to get the eggs to develop to a point where they were ready to be fertilized.

Over the last five years they have worked to find a way around this obstacle and, using mouse embryonic stem cells, they developed a process to help these stem cell-generated eggs mature to the point where they were viable.

In an article in STAT News Richard Anderson, Chair of Clinical Reproductive Science at the University of Edinburgh, said this was a huge achievement: “It’s a very serious piece of work. This group has done a lot of impressive things leading up to this, but this latest paper really completes the in vitro gametogenesis story by doing it in a completely stem-cell-derived way.”

The technique could prove invaluable in helping study infertility in people and, theoretically, could one day lead to women struggling with infertility to be able to use their own stem cells to create eggs or men their own sperm. However, the researchers say that even if that does become possible it’s likely a decade or more away.

While the study is encouraging on a scientific level, it’s raising some concerns on an ethical level. Should there be limits on how many of these manufactured embryos that a couple can create? Can someone create dozens or hundreds of these embryos and then sift through them, using genetic screening tools, to find the ones that have the most desirable traits?

One thing is clear, while the science is evolving, bioethicists, scholars and the public need to be discussing the implications for this work, and what kinds of restraints, if any, need to be applied before it’s RFPT (ready for prime time – OK, I made that one up.)

Delivering a protein to testes could help treat male infertility

Delivering a protein (red fluorescence) to mice testes with a fibroin nanoparticle-encapsulated cationic lipid complex (green) restored male fertility.
Credit: Adapted from ACS Nano 2020, DOI: 10.1021/acsnano.0c04936

For many couples that are ready to start a family, infertility, which is the inability to conceive children, can be a devastating setback. In fact, according to the Mayo Clinic, about 15% of couples are infertile. Of those couples experiencing infertility, one in three are issues related to male infertility, which often involves problems with sperm development.

However, researchers at Seoul National University in South Korea have found a way to deliver an important protein to mouse testes to improve sperm development. This is the first demonstration of direct delivery of proteins into the testes to treat male infertility, which could one day help people.

Male infertility is often associated with a lack of sperm in the semen. This can occur because of damage to the blood-testis barrier (BTB), which protects reproductive cells from harm. A protein named PIN1 is important for proper BTB function.

For this study, male mice were genetically engineered to lack PIN1, making them infertile. The researchers then developed a delivery system called Fibroplex, which consists of sphere-shaped nanoparticles. The team then inserted PIN1 into the Fibroplex, which was subsequently injected into the testes of the infertile mice.

The results were remarkable. The scientists found that the treatment had restored nearly normal PIN1 levels and sperm stem cell numbers in addition to repairing the BTB. The treated mice were also able to father a similar number of pups in comparison to normal mice while untreated, infertile mice weren’t able to reproduce at all. However, the treated mice were only able to successfully reproduce until about 5 months after treatment, at which point the PIN1 was no longer present.

The full results of this study were published in ACS Nano 2020.

Lab-grown human sperm cells could unlock treatments for infertility

Dr. Miles Wilkinson: Photo courtesy UCSD

Out of 100 couples in the US, around 12 or 13 will have trouble starting a family. In one third of those cases the problem is male infertility (one third is female infertility and the other third is a combination of factors). In the past treatment options for men were often limited. Now a new study out of the University of California San Diego (UCSD) could help lead to treatments to help these previously infertile men have children of their own.

The study, led by Dr. Miles Wilkinson of UCSD School of Medicine, targeted spermatogonial stem cells (SSCs), which are the cells that develop into sperm. In the past it was hard to isolate these SSCs from other cells in the testes. However, using a process called single cell RNA sequencing – which is like taking a photo of all the gene expression happening in one cell at a precise moment – the team were able to identify the SSCs.

In a news release Dr. Wilkinson, the senior author of the study, says this is a big advance on previous methods: “We think our approach — which is backed up by several techniques, including single-cell RNA-sequencing analysis — is a significant step toward bringing SSC therapy into the clinic.”

Identifying the SSCs was just the first step. Next the team wanted to find a way to be able to take those cells and grow and multiply them in the lab, an important step in having enough cells to be able to treat infertility.

So, they tested the cells in the lab and identified something called the AKT pathway, which controls cell division and survival. By blocking the AKT pathway they were able to keep the SSCs alive and growing for a month. Next they hope to build on the knowledge and expand the cells for even longer so they could be used in a clinical setting.

This image has an empty alt attribute; its file name is wilkinson-ssc-graphic_450px.jpg
Illustrations by Vishaala Wilkinson

The hope is that this could ultimately lead to treatments for men whose bodies don’t produce sperm cells, or enough sperms cells to make them fertile. It could also help children going through cancer therapy which can destroy their ability to have children of their own later in life. By taking sperm cells and freezing them, they could later be grown and expanded in the lab and injected back into the testes to restore sperm production.

The study is published in the journal Proceedings of the National Academy of Science.

Our Tainted Food Supply: Its Lasting Effects on Stem Cells May Explain Declines in Sperm Counts

Spermatozoons, floating to ovuleIn the science fiction film, Children of Men, humans in the year 2027 face extinction due to decades of infertility. This premise doesn’t seem all that far-fetched when you consider studies in the U.S., Japan, and Europe over the past two decades that point to declining sperm counts. A 2013 study, for instance, that followed 26,000 French men for 17 years reported a 32% drop in sperm counts. And a study of 5000 Danish men with a median age of 19 found 40% had sperm counts corresponding to infertility or decreased fertility.

So what’s going on here? One line of evidence blames exposure to chemicals that leach into our food and water supply. A possible culprit is the much-despised Bisphenol-A, or BPA, a man-made chemical found in plastic bottles, the inner linings of canned food and even receipt paper used at your local grocery store. BPA is known as a hormone disruptor because it interferes with normal hormone activity in the body by mimicking the female hormone estrogen. Lab animals exposed to low levels of BPA have shown increased incidence of certain cancers, neurological problems, diabetes, obesity, female reproduction problems and, yes, decreased sperm counts.

BPA_shutterstock_243369064Data published last week in PLOS Genetics appears to have pinpointed the link between BPA and decreased sperm counts: stem cells. Specifically the so-called spermatogonial stem cells that give rise to sperm. In the Washington State University study, the research team gave newborn male mice daily oral doses of BPA for about two weeks. The chemical exposure negatively affected this spermatogonial stem cell population by disrupting the processing of the cells’ DNA and, in turn, the development of fully mature sperm. The team got similar results replacing BPA with synthetic estrogen found in birth control pills. This form of estrogen is also known to contaminate our water supply even after sewage treatment.

A surprising and even scary twist to these results is that the brief exposure of BPA or estrogen in the newborn male mice permanently changed their stem cells. The team confirmed this observation by transplanting the spermatogonial stem cells from BPA-exposed mice into the testes of mice that never received BPA. In this case, these mice still exhibited reduced sperm production. As senior author Nancy Hunt points out in an interview with Scientific American, the exposure to these chemicals:

“is not simply affecting sperm being produced now, but impacting the stem cell population, and that will affect sperm produced throughout the lifetime.”

It’s remains debatable whether the detectable BPA or estrogen levels in our food and water supply is high enough to actually cause health problems in humans. In 2013 the Food and Drug Administration (FDA) downplayed possible worries on its website:

“Is BPA safe? Yes. Based on FDA’s ongoing safety review of scientific evidence, the available information continues to support the safety of BPA for the currently approved uses in food containers and packaging.”

Still, this recent study and others like it certainly warrant further investigation. University of Missouri scientist Frederick vom Saal, who was not part of the study, put it this way in his interview with Scientific American:

“It’s important in future studies to see if the stem cell changes from exposure are passed to future generations… Since most people are consistently exposed to BPA and other estrogenic compounds, each generation could have it a bit worse.”