Engineered Eggs

Researchers in Japan have reported success in generating mouse eggs or oocytes from pluripotent stem cells. When fertilized, these induced eggs grew into live, healthy pups capable of producing their own offspring. The work is reported in the October 5 issue of the journal Science.

The research team used two different types of pluripotent cells, embryonic and induced. In both cases, they were able to produce cells that are the precursor of the cells of the ovaries, which form eggs. Once they produced these cells and grew them in clusters, they implanted them into the bodies of female mice, where they developed into cell structures that functioned like ovaries. From these reconstituted ovaries, researchers harvested mature oocytes, much as they would for in vitro fertilization (IVF).

The next step, predictably, was to fertilize these eggs and implant them in surrogate mother mice. Once born, the pups developed and were allowed to breed, producing viable offspring.

Pups from ES-oocyte. Female offspring from primordial germ cell-like cell-derived oocytes were fully fertile. Courtesy of Katsuhiko Hayashi.

The most immediate impact of this research will be to advance our understanding of the fundamentals of reproductive biology, especially the development of egg cells. If similar strategies will work with human pluripotent stem cells—especially induced cells—this research may open new approaches for reproductive medicine in the years ahead.

What other possibilities might there be? Again, if the work can be replicated in human beings, two things might happen. Somewhat more remote is the possibility that this strategy will be used for the purposes of human germline modification or so-called “designer babies.” For example, pluripotent stem cells might be genetically modified before they are induced to become the source of oocytes. The modification could be to avoid a disease or for the purposes of enhancement.

More likely, of course, is that this strategy will be used to create human oocytes for research purposes. For example, human induced ovary-like cells could be implanted into a mouse or other nonhuman animal, grown to the right stage of development, then “harvested” in order to collect a significant number of oocytes.

Today, research in certain areas is hampered because of limited supplies of human oocytes. One area that comes to mind is nuclear transfer or cloning. While “Dolly” the sheep is now only a distant memory, this advance brings closer the possibility that with an ample supply of human oocytes for experimentation, researchers will learn how to create human clones reliably.

So the big question is whether this research can be replicated in humans. On that point, here's how the article concludes: "our system serves as a robust foundatin to investige and further reconstitution femaile germline development in vitro, not only in mice, but also in other mammals, including humans."

The article, entitled "Offspring from Oocytes Derived from in vitro Primordial Germ Cell-like Cells in Mice," appears in the 5 October 2012 issue of the journal, Science.

A New Source for New Neurons

The day when stem cell research will give us treatments for common brain disorders such as Parkinson’s or Alzheimer’s just got a little closer. So, by the way, did the day when this research will be used to enhance the capacities of the normal or healthy human brain. The latest advance comes from an international team based mostly in Germany, which has figured out a way to generate new neurons from cells that already exist in the human brain.

The human brain naturally contains specialized cells called pericytes. Usually they are located at the edge of the capillaries that carry blood to the brain. They play a vital role in maintaining the blood-brain barrier.

Neurons. Photo from National Institutes of Health.

Now, thanks to the discovery reported in the October 5 issue of Cell Stem Cell, pericytes might be about to learn a new trick: forming new neurons. Using stem cell reprogramming techniques, researchers learned that two factors—Sox2 and Mash1—would induce pericytes to change their developmental state and begin to function as newly-formed neurons.

According to the article, “these induced neuronal cells acquire the ability of repetitive action potential firing and serve as synaptic targets for other neurons, indicating their capability of integrating into neuronal networks.” In other words, they do what neurons normally do. They process signals from one end of the cell to another. They form synaptic connections with other neurons. And they integrate into larger networks.

Will this become a new strategy for treating diseases or injuries to brain cells? That is the hope, but difficult challenges remain. How can living pericytes in a functioning human brain be targeted and induced to become neurons? If they generate new neurons, will they function properly? Will they integrate themselves into a functioning brain, preferably taking up the cognitive processes that are lost because of disease or injury?

The authors conclude that “much needs to be learned” but that “our data provide strong support for the notion that neuronal reprogramming of cells of pericytic origin within the damaged brain may become a viable approach to replace degenerated neurons.”

According to Benedikt Berninger of the Johannes Gutenberg University in Mainz, a leader in the research team, “The ultimate goal we have in mind is that this may one day enable us to induce such conversion within the brain itself and thus provide a novel strategy for repairing the injured or diseased brain."

That may be the goal, but it's hard to imagine this research will be limited to therapy. In fact it may turn out to be easier to use it to enhance the cognitive capacity of normal or healthy aging brains than it is to treat disease. Anything that stimulates the growth of new neurons is likely to be very appealing to aging adults.

If human stem cell research is to reach its full promise, many more advances like this will have to occur. With each advance, however, comes growing confidence that the promise of the field may be highly challenging, but it is not hype.

The article entitled “Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells” is published in the October 4, 2012 issue of Cell Stem Cell.

Stem Cell Update: Important Research Breakthrough

Another important step has just been taken toward achieving the medical promise of stem cell research. For the first time, researchers at the Max Planck Institute for Molecular Biomedicine in Münster, Germany, have reprogrammed skin cells directly into multipotent stem cells.

Over the past five years, stem cell researchers have learned how to induce or reprogram skin cells to become pluripotent stem cells—cells capable of becoming any type of cell in the body. The result: induced pluripotent stem cells or iPSCs. Scientists have also discovered how to reprogram cells to become precursor or progenitor cells. Precursor cells have a much narrower range of potential for development. They are able to become one very specific type of cell in the body.

Expanding on previous work, the latest breakthrough achieves a kind of “goldilocks” or just-right level. Working with mice, the team led by Hans Schöler discovered how to reprogram fully differentiated skin cells into neuronal stem cells (NSC)s. Unlike pluripotent cells, NSCs are far more suitable for clinical use. And now, with this breakthrough, the Max Plank Institute team has learned how to reprogram or induce NSCs or iNSCs.

And unlike precursor or progenitor cells, iNSCs are capable of multiplying and diffentiating once they are implanted. When researchers implanted their iNSCs into mouse brains, iNSCs generated new cells that began to take on some of the characteristics of ordinary developing brain cells.

Caption: This is an immunofluorescence microscopy image of the induced neural stem cells (iNSCs) using antibodies against two neural stem cell markers SSEA1 (red color) and Olig2 (green color). Credit: MPI for Molecular Biomedicine

The field of stem cell research has faced many obstacles, some moral and some medical. The main moral objection is that the prime source of human pluripotent cells is the human embryo, and many object to the destruction of the embryo for medical purposes. One of the medical challenges is that implanted cells are likely to be rejected by the immune system, much as transplanted organs are rejected unless immunosuppressant drugs are given.

Unless, of course, the source of the cells is from the patient’s own body. That’s why this achievement is important. If this technique can be applied to human cells—and there’s no reason to think it can’t—then someday it may be possible to take a small sample of cells from a patient’s skin, convert them to iNSCs, and then implant them in the patient’s brain to repair damage from disease or injury.

Not only does the iNSC discovery use the patient’s own cells as the source. It also by-passes the pluripotent stage. That fact should help researchers avoid creating cancer or other problems.

According to Schöler, "pluripotent stem cells exhibit such a high degree of plasticity that under the wrong circumstances they may form tumours instead of regenerating a tissue or an organ."

"Our research shows that reprogramming somatic cells does not require passing through a pluripotent stage," Schöler said in a press release issued by the Max Plank Institute. "Thanks to this new approach, tissue regeneration is becoming a more streamlined—and safer—process."

The article, "Direct Reprogramming of Fibroblasts into Neural Stem Cells by Defined Factors," appears in the March 22 issue of Cell Stem Cell.