Scientists at the University of Cambridge working with the Weizmann Institute have created primordial germ cells - cells that will go on to become egg and sperm - using human embryonic stem cells. Although this had already been done using rodent stem cells, the study, published today in the journal Cell, is the first time this has been achieved efficiently using human stem cells.

When an egg cell is fertilised by a sperm, it begins to divide into a cluster of cells known as a blastocyst, the early stage of the embryo. Within this ball of cells, some cells form the inner cell mass - which will develop into the foetus - and some form the outer wall, which becomes the placenta. Cells in the inner cell mass are 'reset' to become stem cells - cells that have the potential to develop into any type of cell within the body. A small number of these cells become primordial germ cells (PGCs) - these have the potential to become germ cells (sperm and egg), which in later life will pass on the offspring's genetic information to its own offspring.

"The creation of primordial germ cells is one of the earliest events during early mammalian development," says Dr Naoko Irie, first author of the paper from the Wellcome Trust/Cancer Research UK Gurdon Institute at the University of Cambridge. "It's a stage we've managed to recreate using stem cells from mice and rats, but until now few researches have done this systematically using human stem cells. It has highlighted important differences between embryo development in humans and rodents that may mean findings in mice and rats may not be directly extrapolated to humans."

Professor Surani at the Gurdon Institute, who led the research, and his colleagues found that a gene known as SOX17 is critical for directing human stem cells to become PGCs (a stage known as 'specification'). This was a surprise as the mouse equivalent of this gene is not involved in the process, suggesting a key difference between mouse and human development. SOX17 had previously been shown to be involved in directing stem cells to become endodermal cells, which then develop into cells including those for the lung, gut and pancreas, but this is the first time it has been seen in PGC specification.

The group showed that PGCs could also be made from reprogrammed adult cells, such as skin cells, which will allow investigations on patient-specific cells to advance knowledge of the human germline, infertility and germ cell tumours. The research also has potential implications for understanding the process of 'epigenetic' inheritance. Scientists have known for some time that our environment - for example, our diet or smoking habits - can affect our genes through a process known as methylation whereby molecules attach themselves to our DNA, acting like dimmer switches to increase or decrease the activity of genes. These methylation patterns can be passed down to the offspring.

Professor Surani and colleagues have shown that during the PGC specification stage, a programme is initiated to erase these methylation patterns, acting as a 'reset' switch. However, traces of these patterns might be inherited - it is not yet clear why this might occur.

"Germ cells are 'immortal' in the sense that they provide an enduring link between all generations, carrying genetic information from one generation to the next," adds Professor Surani. "The comprehensive erasure of epigenetic information ensures that most, if not all, epigenetic mutations are erased, which promotes 'rejuvenation' of the lineage and allows it to give rise to endless generations. These mechanisms are of wider interest towards understanding age-related diseases, which in part might be due to cumulative epigenetic mutations."

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Egg and sperm race: Scientists create precursors to human egg and sperm

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Some hope that sperm cells could one day be derived from the skin cells of a man who is otherwise sterile and that a similar process cold produce viable egg cells from a sterile woman's body.

Israeli and UK researchers have created human sperm and egg precursor cells in a dish, starting from a person's skin cells. The achievement is a small step towards a treatment for infertility, although one that could face significant controversy and regulatory hurdles.

The experiment, reported online in Cell on 24 December1, recreates in humans parts of a procedure first developed in mice, in which cells called induced pluripotent stem (iPS) cells reprogrammed cells that can differentiate into almost any cell type are used to create sperm or eggs that are subsequently manipulated to produce live births by in vitro fertilization.

In 2012, stem-cell biologist Mitinori Saitou of Kyoto University in Japan and his collaborators created the first artificial primordial germ cells (PGCs)2. These are specialized cells that emerge during embryonic development and later give rise to sperm or eggs. Saitou made them in a dish, starting with skin cells reprogrammed to an embryonic-like state through iPS-cell technology (see 'Stem cells: Egg engineers'). They also were able to achieve the same result starting with embryonic stem cells.

Although his cells could not develop beyond this precursor stage in the dish, Saito found that if he placed them in mouse testes, they would mature into sperm, and if he placed them in ovaries, they would mature into functional eggs. Both sperm and eggs could be used for in vitro fertilization.

Efforts to engineer similarly functional gametes in humans have produced PGC-like cells, but with such a low efficiency success rate of turning stem cells into gametes that it was difficult for others to expand on the work.. Previous efforts also required the introduction of genes that would render the cells unusable in the clinic.

Ewen Callaway reports on the ethical challenges of using lab-made sperm and egg cells in fertility treatments.

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Now a team led by Azim Surani of the University of Cambridge, UK, and Jacob Hanna of the Weizmann Institute of Science in Rehovot, Israel, has replicated the in vitro portion the first half, says Hanna of Saitous efforts in humans.

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Rudimentary egg and sperm cells made from stem cells

Physician-scientists at OHSU Doernbecher Children's Hospital reveal a high-fat diet and obesity during pregnancy compromise the blood-forming, or hematopoietic, stem cell system in the fetal liver responsible for creating and sustaining lifelong blood and immune system function.

The life-long burden of a western-style diet on the heart and circulatory system have long been appreciated. However, prior to this study, no one had considered whether the developing blood stem cells might be similarly vulnerable to prenatal high-fat diet and/or maternal obesity. The findings are published in the journal Molecular Metabolism.

"Our results offer a model for testing whether the effects of a high-fat diet and obesity can be repaired through dietary intervention, a key question when extrapolating this data to human populations," said Daniel L. Marks, M.D., Ph.D., co-investigator and professor of pediatric endocrinology in the OHSU School of Medicine and Pap Family Pediatric Research Institute at OHSU Doernbecher Children's Hospital.

Several years ago, Marks and colleagues developed a mouse model that closely mimics the high-fat, high-simple-sugar diet currently consumed by many young women of childbearing age. Their subsequent research demonstrated that maternal overnutrition in mice significantly reduced the size of the fetal liver.

Armed with this information, Marks partnered with another stem cell expert, Peter Kurre, M.D., co-investigator on the current study and professor of pediatric oncology in the OHSU School of Medicine and the Pap Family Pediatric Research Institute at OHSU Doernbecher Children's Hospital.

Together, they discovered that the complex changes that occur as a result of maternal high-fat diet and obesity put significant constraints on the growth and expansion of blood stem cells in the fetal liver, which ultimately compromises the developing immune system.

"In light of the spreading western-style, high-fat diet and accompanying obesity epidemic, this study highlights the need to better understand the previous unrecognized susceptibility of the stem and progenitor cell system," Kurre said. "These findings may provide broad context for the rise in immune disease and allergic disposition in children."

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High-fat diet, obesity during pregnancy harms stem cells in developing fetus

British researchers say they've gotten embryonic stem cells to turn into precursors to reproductive cells

WebMD News from HealthDay

By Robert Preidt

HealthDay Reporter

WEDNESDAY, Dec. 24, 2014 (HealthDay News) -- Researchers say they have used human embryonic stem cells to create cells that develop into eggs and sperm.

While this had already been done using rodent stem cells, this is the first time that these types of cells -- called primordial germ cells -- have been produced efficiently using human stem cells, according to the team at the University of Cambridge in England.

"The creation of primordial germ cells is one of the earliest events during early mammalian development," study first author Naoko Irie said in a university news release.

"It's a stage we've managed to recreate using stem cells from mice and rats, but until now few researchers have done this systematically using human stem cells. It has highlighted important differences between embryo development in humans and rodents that may mean findings in mice and rats may not be directly extrapolated to humans."

The study is published in the Dec. 24 issue of the journal Cell.

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Scientists Get Closer to Producing Egg, Sperm From Stem Cells

Scientists have made primitive forms of artificial sperm and eggs in a medical feat that could transform the understanding of age-related diseases and fertility problems.

Researchers in Cambridge made the early-stage sex cells by culturing human embryonic stem cells under carefully-controlled conditions for a week.

They followed the success by showing that the same procedure can convert adult skin tissue into precursors for sperm and eggs, raising the prospect of making sex cells that are genetically matched to patients.

The cells should have the potential to grow into mature sperm and eggs, though this has never been done in the lab before. The next step for the researchers will be to inject the cells into mouse ovaries or testes to see if they fully develop in the animals.

British law prohibits fertility clinics in the UK from using artificial sperm and eggs to treat infertile couples. But if the law was revised, skin cells could potentially be taken from patients and turned into genetically identical sperm or eggs for use in IVF therapies.

Skin cells from a woman could only be used to make eggs because they lack the Y chromosome. Those from a male might theoretically be turned into eggs as well as sperm, but Azim Surani, who led the work at the Gurdon Institute in Cambridge, said that on the basis of current knowledge, that was unlikely.

Its not impossible that we could take these cells on towards making gametes, but whether we could ever use them is another question for another time, Surani told the Guardian.

Researchers have made sperm and eggs from rodent stem cells before but have struggled do the same with human cells. In 2012, Japanese scientists created mouse eggs from stem cells and used them to make baby mice. Three years earlier, scientists at Newcastle University claimed to have made human sperm from stem cells, but their scientific paper was retracted amid allegations of plagiarism. In 2002, US researchers produced male and female mouse pups from male stem cells.

Suranis team tried a number of different approaches before hitting on a culture process that turned up to half of the human stem cells in the dish into precursors of sperm and eggs. Over the five day process, the scientists added natural chemicals called growth factors to nudge the cells in the right developmental direction.

Its remarkably fast. We can now take any embryonic stem cell line and once we have them in the proper conditions, we can make these primordial cells in five to six days, Surani said. Details of the work, a collaboration with the Weizmann Institute in Israel, are published in the journal, Cell.

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Scientists use skin cells to create artificial sperm and eggs