By David N. Leff

The cuckoo bird (Cuculus canoris) is famous - or infamous - for laying its eggs in other birds' nests. Stem cells - the primordial developmental cells that give rise to the embryo's organ systems - are reputedly more virtuous. That is, an immature blood-forming stem cell will make muscle, not blood. To cell biologists, such cellular adultery sounds like a cuckoo idea.

But that stem-cell dedication to keeping faith with its own progeny cells is not necessarily perfect, as very recent research shows. "Nobody categorically came out and said stem cells must be dedicated to their tissue of origin," observed stem cell biologist Ihor Lemischka, at Princeton University. "That was just the unspoken consensus feeling that arose in the field over the years. Few would have thought of doing these kinds of surprising experiments."

The latest such deviant research is reported in today's Proceedings of the National Academy of Sciences (PNAS), dated Dec. 7, 1999, under the title: ""Hematopoietic [blood-forming] potential of stem cells isolated from murine skeletal muscle." Its senior author is stem cell biologist Margaret Goodell, at Baylor College of Medicine in Houston.

Lemischka wrote the accompanying commentary, quizzically headed, "The power of stem cells reconsidered?" He told BioWorld Today, "The Goodell paper's significance might well be that it's possible to grow blood-forming stem cells if you isolate them from a different source, in this case, muscle. What's really surprising about that paper," he added, "is that there's a huge effort in the hematopoietic stem cell community - particularly in the human clinical community - to achieve the expansion of transplantable stem cell populations ex vivo or in vitro.

"It's only recently," Lemischka went on, "that a number of these systems have actually yielded some encouraging results. On the other hand, you have somebody who comes at this sort of out-of-left-field experiment, where Goodell's lab took cells from muscle and stuck them into culture. And after five days in culture they're getting hematopoietic transplantable activity that is 10 times enhanced on a per-cell basis over what is found in fresh bone marrow. I think that's the most intriguing thing about that paper."

Muscle Stem Cells Begat Blood-Forming Progeny

"In a biological sense," the Princeton biologist continued, "clearly to be able to demonstrate that you have blood-forming ability in muscle, and muscle-forming ability in bone marrow, speaks to a possible greater flexibility in the differentiation capacity of classically considered stem cell populations. And that would be the counter-traditional thing."

"Scientists used to think," Goodell observed, "that blood cells came from blood cells only, and muscle cell from muscle cells only. We've now shown that there are stem cells in skeletal muscle that can generate blood. This suggests that the natural function of the muscle stem cells can be changed from becoming one type of cell to another."

What encouraged the Baylor co-authors to strike out in this off-base direction." Goodell told BioWorld Today, "were some hints we got from the literature. The primary one, in Science 18 months ago, was that a group I knew transplanted whole bone marrow, where blood is formed, and found it could give rise to differentiated muscle cells. That work prompted me to ask the question whether there would be cells in the muscle that could differentiate into bone marrow."

The co-authors injected two types of murine stem cells into the bloodstream of young adult mice: muscle cells taken from adult animals and carrying genetic tracer markers. Six weeks and again 12 weeks later, they analyzed adult blood cells from the recipient rodents to pinpoint their origin. The team found, to its surprise, that as many or more blood cells had arisen from the marked muscle cells as from the bone-marrow ones.

Goodell favors the hypothesis that both stem cell types "shared some common receptors, and when put in a different environment - the bloodstream - the right combination of muscle cell receptors was stimulated, causing their differentiation into hematopoietic cells." She believes, at least in theory, the process could work backward as well as forward. "It's also possible," she pointed out, "that it could work in other stem cells besides muscle and blood - perhaps brain, liver, lungs and so on. A lot of people are wondering about that at this very moment."

Clinical Uses 'Remain To Be Seen'

On Sunday, Goodell reported her current experimental findings to the American Society of Hematology meeting in New Orleans. Besides what she and her co-authors covered in their PNAS paper, she recalled that, "yesterday in my presentation, I discussed that we had looked at fresh muscle cells as well as cultured ones. Both have a similar activity, but the fresh a little less.

"The clinically related question I'd like to resolve," she observed, "is whether human tissue has the same activity as the mice in our experiments." Goodell foresees that "the uses for bone marrow transplantation will expand, so people will start using it for non-hematopoietic diseases, such as muscular dystrophy."

"The potential for muscular dystrophy," Lemischka opined, "is that if you could show that injecting muscle-forming activity intravenously, and systemically allow these stem cells to go to multiple muscle sources or locations in a human patient, it would be a way - if efficiency were much improved - to show you could cure the disease this way. (See BioWorld Today, Sept. 23, 1999, p. 1.)

"In terms of gene therapy, perhaps," he went on, "if it's true that these muscle cells are actively growing - replicating and dividing in these cultures - not just hanging out or changing in some way to acquire blood-forming ability, that's one prerequisite to introducing novel genetic material via traditional retroviral vectors. There are practical issues here that are interesting.

"My own feeling," Lemischka concluded, "is that it's only a matter of time really. Cell-based therapies are going to be very important in the future. While I am obviously excited about the data in these papers and their clinical implications, how fast they get into the clinic remains to be seen."