Previous leading-edge work by Shinya Yamanaka (Kyoto University, Japan) in 2008 made the dramatic leap of inducing pluripotent stem cells from skin fibroblast cells (the structural cells that hold the skin together). This was the first time that pluripotent stem cells (stem cells that can, in turn, become almost any kind of adult cell) were manufactured without using embryonic stem cells. The approach avoided the ethical and religious issues involved with anything embryonic. Significantly for the field of stem cell research, Dr. Yamanaka’s work also exposed the role of a particular protein, called OCT4, which is encoded by the POU5F1 gene and is an important factor in reprogramming the adult cells (now called Yamanaka factors).

Dr. Bhatia and his team started by collecting skin fibroblast cells from several volunteers. The fibroblast cells were injected with a virus that ‘inserted’ (really a form of controlled infection) the gene POU5F1 into the DNA of each cell. This causes the cells to produce the OCT4 protein. The protein provides the chemical pathway to controlling the growth and nature of the cell. The control was developed by growing the cells in a soup of appropriate chemicals, most of them cytokines, which are signaling proteins that direct cell activity for growth and immunity.

During the process, multipotent cells (or progenitor cells) are produced. These are cells that are restricted in what type of cell they can become (in this case, blood cells) but they can become several kinds of those cells. By tweaking the cytokine mixture, the research team was able to produce the three major classes of blood cells: White, red, and platelet.

To spell out the significance of directly converting one adult cell type to another adult cell type:

1. Bypassing the stage of pluripotent stem cell production obviously simplifies the procedure.
2. The cells produced are completely ‘adult’ cells, needing no further reprogramming.
3. Removing the pluripotent stage reduces the risk of introducing tumor causing mutations.
4. With no stem cells involved, there is no moral hazard.
5. A person’s own skin cells can be used to produce a variety of blood cells, removing the danger of rejection.
6. It demonstrates the potential for converting many types of cells.

With so many plusses – and so much potential – this is the kind of research that has earned the laudative ‘breakthrough.’

Of course, the story isn’t finished. So far the converted cells have only been tested in mice. It remains to be seen if the blood cells can be used in humans. There have been problems with the viability (especially long term) for some of the uses of stem cells. At this point, it is unknown if the reprogrammed cells have any peculiarities. A real concern is whether the artificially produced cells will react normally in the epigenetic environment of living human cells. That is the utterly complex and as yet poorly understood interaction between DNA and the proteins that guide its expression to adapt to existing conditions.

As Dr. Bhatia and his team are well aware, there are many steps ahead before even contemplating trials of blood in human beings. For one thing, they must develop a method for producing converted cells in quantity. The current procedure works well in a Petri dish, so to speak, but may run in complications with attempts to scale up production. Once the quantities are sufficient, then use in screening drugs and other experimental procedures are ahead.

The ultimate test would be transplanting the cells into humans, says Bhatia, but that isn’t on the cards — at least not yet. “The clinical side is going to be a lot of work,” he says. “At least from our estimation, this is the most encouraging result we’ve seen for using blood cells for cell-replacement therapy.”

[Source: Nature, News]

Unfortunately, with all the noise the quietly important may go unnoticed. When I see this headline: Researchers directly turn mouse skin cells into neurons, skipping iPS stage; it’s likely to go floating past my consciousness without even dragging its feet. There are so many stories these days involving creation of this or that stem cell, or of turning this or that stem cell into some other type of cell. All of them promise to make creation of stem cells easier, or the use of stem cells to replace/repair this or that body cell. Each announcement represents one of a thousand steps, a few of which will certainly lead to important medical procedures, but for now just a lot of ‘attaboys!’ for the scientists toiling on their research agenda.

I bet you’ve already forgotten the ‘Researchers directly turn mouse skin cells into neurons, skipping iPS stage.’ It could be you’re unfamiliar with the abbreviation iPS. It stands for induced Pluripotent Stem cell. Pluripotent stem cells can turn into almost any kind of cell. They’re not as flexible that way as embryonic or totipotent stem cells, but close. When a researcher ‘induces’ a pluripotent stem cell, it means they take a typical ‘adult cell’ – one that has already undergone differentiation to become a specific type of cell, say a skin cell – and one way or another forces it to become a stem cell of the pluripotent variety. Stem cell research is full of attempts to create cells from anything other than embryonic stem cells, largely because of the controversy and ethical uncertainty of using cells from human embryos. The typical approach is: Take a mouse cell, a skin (epithelial) cell, and induce it to become a pluripotent cell. Then take the iPS cell and turn it into another kind of cell, for example, a neuron. This seems logical, since differentiating a pluripotent (or embryonic) stem cell is what these cells are meant to do.

This two phase method, with many steps, is time consuming. What if you could go directly from an adult cell, the skin cell, and turn it into a neuron, without going through the iPS phase? Obviously it would be quicker, but most researchers would say, ‘It doesn’t work that way.’ Ah, but it can.

To make this ‘unprecedented’ transformation, it’s necessary to get down and molecular to alter a few genes. But which genes? This is where the researchers at Stanford University (California, USA) started to earn their grant money. They began with a candidate list of 19 genes in mice, all involved with epigenetic reprogramming or neural development. They altered these genes in a virus (lentivirus) and injected the virus into the skin cells of mice. In just over a month some cells developed properties associated with neurons. Further testing narrowed the genes down to just three, and when these were altered and injected, about 20% of the skin cells from the tail of mice became functional neurons.

This was astonishing in (at least) two respects: The rate of cell differentiation success, 20%, is phenomenally high. Typically only 1-2% of adult cells can be induced to become pluripotent. Second, the speed was also extraordinary, just a week as compared to many weeks for the iPS procedure. Faster, better, cheaper – take all three. As one of the researchers put it:

“We actively and directly induced one cell type to become a completely different cell type,” said Marius Wernig, MD, assistant professor of pathology and a member of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. “These are fully functional neurons. They can do all the principal things that neurons in the brain do.” That includes making connections with and signaling to other nerve cells — critical functions if the cells are eventually to be used as therapy for Parkinson’s disease or other disorders.
…
“We were very surprised by both the timing and the efficiency,” said Wernig. “This is much more straightforward than going through iPS cells, and it’s likely to be a very viable alternative.” Quickly making neurons from a specific patient may allow researchers to study particular disease processes such as Parkinson’s in a laboratory dish, or one day to even manufacture cells for therapy.

The research suggests that the pluripotent stage, rather than being a required touchstone for identity-shifting cells, may simply be another possible cellular state. Wernig speculates that finding the right combination of cell-fate-specific genes may trigger a domino effect in the recipient cell, wiping away restrictive DNA modifications and imprinting a new developmental fate on the genomic landscape.

“It may be hard to prove,” said Wernig, “but I no longer think that the induction of iPS cells is a reversal of development. It’s probably more of a direct conversion like what we’re seeing here, from one cell type to another that just happens to be more embryonic-like. This tips our ideas about epigenetic regulation upside down.”

[Source: EurekAlert]

That last line, “…tips our ideas about epigenetic regulation upside down” is the kicker, potentially the initial words of a call to ‘revolution.’ He’s saying, modestly, that stem cell scientists may have it all wrong. In the domain of cell differentiation, any cell can go any which way, it all depends on the genetics, the genetics depend on their expression (epigenetic regulation), and could be added, expression is keyed to both the DNA and the environment.

How serious are the Stanford researchers about their findings? They’ve applied for a patent on the technique.

Researchers converted human skin cells into induced pluripotent stem cells and then converted the stem cells into liver cells that were able to function in the livers of mice.

Scientists at The Medical College of Wisconsin in Milwaukee have successfully produced liver cells from patients’ skin cells opening the possibility of treating a wide range of diseases that affect liver function. The study was led by Stephen A. Duncan, D. Phil., Marcus Professor in Human and Molecular Genetics, and professor of cell biology, neurobiology and anatomy, along with postdoctoral fellow Karim Si-Tayeb, Ph.D., and graduate student Ms. Fallon Noto.

This result shows that induced pluripotent stem cells can be converted into useful functioning cells. Still a lot of work to do to prove these cells are safe and effective in the long term. But this is a good step.
[Source: FuturePundit]