stem cells

Credit: NIH Stem Cell Unit

So many controversies about stem cells have flared and died away over the past decade that it can be hard to keep track of them all. The most recent contretemps, as evidenced by reports in the scientific press here, here and here, is about an exceedingly rare (and perhaps non-existent) group of diminutive cells called Very Small Embryonic Like cells, or VSELs (pronounced vee sells) for short.

Depending on whom you believe, VSELs could be a dogma-busting game changer for stem cell therapy or, as a scientific report published in Stem Cell Reports yesterday strongly implied, just another fanciful claim that cannot be reproduced and so deserves to be forgotten. We could all wait a few years for the science to mature to get a satisfactory answer, but neither government funders nor impatient biotech venture capitalists are likely to tarry that long before choosing whether to back VSELs or move on to something else that is also, maybe, perhaps, someday, possibly going to work.

So whats all the fuss about this time? In 2006, Mariusz Ratajczak and his colleagues at the University of Louisville published a report claiming that they had found very small cells in the bone marrow of adult mice that had some of the properties of adult stem cells but didnt quite look or act like the hematopoietic stem cells normally found in the bone marrow. (Hematopoietic stem cells, like all adult stem cells, normally give rise to a limited number of tissues, in this case, red blood cells, platelets and the various kinds of white blood cells or lymphocytes that are found throughout the body.) For one thing, these new cells were very smallon the order of 3 microns, which is indeed minute, especially when compared to the smallest white blood cells, which are about 8 to 10 microns.

Another puzzling feature of VSELs, according to Ratajczak and his team, is that they dont divide and create more copies of themselves the way normal stem cells doeven after investigators dumped a bunch of growth factors on them that have been shown to push other stem cells into recreating themselves. Indeed, you could hardly think of VSELs as stem cells at allsince regenerating themselves is one of the most important hallmarks of stem cells.

But, Ratajczak says, further research in his lab hinted at an intriguing possibilityevidence that VSELs contain certain molecules on their surface that indicate that they are quiescent stem cells (think long-term stasis) left over from the earliest stages of embryonic development. You would expect to have a tough time waking these cells and getting them to regenerate, he notes.

Imagine if leftover cells from when you were an embryo, which kept the potential to become any type of tissue, randomly started becoming active in your body. How could you stop them from taking over? Any evolutionary pathway that permitted VSELs to easily regenerate would quickly turn into a fast track to a lethal tumor. For these and other reasons, Ratajczak says, its entirely possible that VSELs may not be able to grow outside the body. Or perhaps they are only active in childhood, giving rise to some of the tremendous recuperative powers of youngsters. If so, they might prove fascinating but not terribly commercially valuable.

If, on the other hand, a scientist could figure out how to prod VSELS in adults to regenerate themselvesand to differentiate into different cell typeshe or she would have found the proverbial Holy Grailfully functional embryonic stem cells that come from adults instead of embryos. Not only would such an accomplishment avoid a lot of the ethical problems that some people have with the current sources of embryonic stem cellsnamely embryosbut fully functional VSELs would eliminate the sorts of rejection problems that clinicians always have to look out for when transplanting bone marrow or other solutions made up of stem cells.

For a while there, it looked as though Ratajczaks lab was the only one capable of isolating VSELs from micenever a good sign if you want to convince other researchers that youve found something new and different. Besides being quite small, the cells are very rare, Ratajzak says, making them very difficult to isolate.

Then the Vatican donated $1 million through a foundation to fund work being done on VSELs by a company called NeoStemwhich is also not necessarily the best PR if youre trying to win over skeptical stem cell scientists who have been repeatedly battered by church-state fights over the morality of harvesting stem cells from embryos.

Indeed, more than one stem cell researcher has suggested the interest in VSELs has more of an ideological rather than a scientific underpinning. I dont understand this, Ratjczak told me when I asked him about the possibility. I am very far from any Vatican people. I am an atheist actually.

Although two groups have reported in the past two years that they could not replicate Ratjczaks work, two other groups have now claimed to have found VSELs. After sending a post-doctoral fellow to Louisville to master the technique, Diane Krause, a stem cell researcher at Yale University, led a team of investigators who managed to isolate their very own VSELs from the bone marrow of mice. It was very challenging, Krause says. We had to keep checking with Mariuscz on how to do things.

The Yale team was subsequently able to coax these cells into becoming more specialized cells (called epithelial cells) of the sort that line the various passageways of the lungs. If their results can be verified, it would lend crucial support to the special nature of VSELs since stem cells from bone marrow dont usually give rise to epithelial cells.

In addition, Russell Taichman, a professor of dentistry at the University of Michigan, says he has found a very similar kind of cell. Later, when he met up with Mariusz Ratajczak at a conference, Taichman says, we shared our experiments and it looks like were looking at the same thing.

Credit: Niels Geijsen, Massachusetts General Hospital/National Science Foundation

Irving Weissman, a pioneer in the field of hematopoietic stem cells and the director of the Institute of Stem Cell Biology and Regenerative Medicine at Stanford University, is having none of this. What it really comes down to is when you do evidence-based research and publish evidence-based research, is it reproducible in independent hands? says the co-author of the recent research paper in Stem Cells Report. We tried to be as careful as we could to see if we could reproduce the findings and we cant. Were a pretty good lab at sorting cells. Were a pretty good lab at hematopoiesis. Part of the responsibility of a scientist is to publish things so that any lab competent in the art can reproduce it and we couldnt.

When I playfully suggested that lack of evidence wasnt the same as proof of a negative, Weissman nimbly switched gears. Send us VSELs for us to test, so that we dont make the mistake of isolation. Wed be happy to evaluate them.

Naturally, I then repeated Weissmans words to Ratajczak, who was in Poland to attend a meeting. Why didnt Dr. Weissmans people contact us three or four months ago when they were having trouble? Ratajczak said. And now he wants to collaborate? And then in a less frustrated tone of voice: Okay, he can come and see me any time.

Weissman is not the only skeptic. They [Ratajczak and colleagues] are obviously measuring something. But its difficult to say what, Christine Mummery, a professor of developmental biology at Leiden University in the Netherlands told a reporter for Cell Stem Cell. As long as these cells remain rather odd and the experiments that are published seem slightly less than robust, I think theyre open to question.

So who to believe? Do VSELs exist or not? I trust Mariusz Ratajczaks papers and I trust anything that Irv Weissman is doing, Krause says. I know there has to be some objective explanation for the difference but I dont know what that explanation is.

We are right and you will see, Ratajczak says. The truth will prevail.

Were in this endless round of having to test these things, Weissman says. When I ask him if VSELs are a distraction, he replies, I know its a distraction.

Stay tuned. I dont think weve heard the end of VSELs.