By David N. Leff

White cells and red cells ¿ the leukocytes, lymphocytes and erythrocytes ¿ originate in the bone marrow.

When one of these turns cancerous, as in leukemia or myeloma, transplantation of healthy cells from an immunocompatible donor may be in order. In such cases, the patient¿s body is first bombarded with ionizing radiation to kill off the malignant cell population, including the blood-forming hematopoietic stem cells that give rise to those errant blood constituents.

¿The standard human marrow transplant source is now mobilized peripheral blood rather than bone marrow,¿ observed stem cell pathologist Irving Weissman, at Stanford University in California. ¿That comes from experiments by clinicians, not us scientists, which showed that in cancer patients getting cytoreduction treatment, they¿ve mobilized cells into the blood stream that had blood-forming potential ¿ and even went on to use as transplants. That takes advantage of a process that was already there. So it answers the question nobody even asked any more until I did: Why do bone marrow transplants work?¿¿

Weissman is senior author of a paper in today¿s Science, dated Nov. 30, 2001. It¿s titled: ¿Physiological migration of hematopoietic stem and progenitor cells.¿

¿The beginning point of all of our studies,¿ Weissman told BioWorld Today, ¿is to know that we have hematopoietic stem cells, and also their two daughter cells ¿ the short-term stem cell (STSC) and the multipotent progenitor (MPP). We¿ve defined them both by surface markers and antibodies, so we can isolate and enumerate them, and always functionally, by what they do.

¿Our main finding in Science,¿ he continued, ¿is based on a fact we¿ve known for years: that there were cells capable of blood formation ¿ really, stem cells ¿ present in rare numbers in the body¿s blood stream. The major significance is that even though there are only small numbers in the circulation, they have a residence time there of just minutes. So for the bone marrow, which makes the hematopoietic stem cells, to keep them at that level in the blood stream over a full day, a very large number of blood-forming stem cells and their two progenitors, STSC and MPP, have to be moved from the marrow to the blood, and then of course from the blood to some other tissue in the body.¿

Parabiosis: Two Mice That Bleed As One

¿Therefore, we¿ve shown,¿ Weissman went on, ¿that a large number of stem cells are coursing through the blood every day. By parabiosis experiments, where we tied the blood vessels of two mice together, the cells in the blood normally do go back into the bone marrow, engraft there, and participate in the next animal¿s blood formation. So it turned out to be a much more dynamic system than any of us expected.¿

By means of microsurgery, the team joined the blood vessels in pairs of mice with slightly differing surface white blood cell molecules into a common intercommunicating circulation system.

¿We wanted to be able to understand in the most physiological setting,¿ Weissman said, ¿whether the cells that we found in the blood stream were significant for the life of the animal. The residence-time experiments gave us the clue that these cells, once in the blood stream, really don¿t stay there very long. Therefore, large numbers of cells must be going through the circulation every day at that level.

¿Some critics might say,¿ he suggested, ¿Sure, we found hematopoietic stem cells in the blood, but those are the ones on their way to die  so they¿re functionally meaningless.¿ Quite the contrary. Our parabiotic results showed that they were functionally meaningful. We didn¿t have to irradiate an animal; we didn¿t have to do anything to it to get it to accept cells coming from its partner via the blood stream and going into the marrow to engraft. That was the most important question that the parabiotic experiments answered.¿

Since submitting their paper to Science early last summer, Weissman and his co-authors have been working on three projects:

¿First, we are trying to nail down the surface markers on those stem cells in the blood stream to see if they will give us a clue as to the homing receptors for the bone marrow. We¿re pretty close to that, though it¿s not published yet. The second thing we¿re doing is asking: Say, we have created a mouse where by transplant we put in a single blood-forming stem cell that was genetically marked and visible. Could we follow when it¿s transplanted, how long it takes once it occupies one bone marrow niche to create others by this circulation technique?¿

¿And the final thing we¿re doing is to ask whether very highly purified stem cells in some cases could give rise to liver. At first, we thought that by testing we would show that it wasn¿t true, because I had such a high suspicion of all those published transdifferentiation reports ¿ fat to blood, brain to blood, muscle to brain, muscle to blood, and so on and on and on. But we found that in fact it did work. Now we want to find out if this special stage of the stem cells¿ lifespan, when it¿s in the blood, could potentially regenerate the liver. We don¿t know yet where that¿s going.¿

From Bone Marrow To Liver

Weissman is associated with two biotechnology companies. In 1988, he co-founded SyStemix Inc., located in the Stanford Industrial Park, Palo Alto, Calif. He also co-founded StemCells Inc., now merged with Gene Therapy Inc., of Gaithersburg, Md.

¿At Systemix, we did blood-forming stem cells,¿ Weissman said. ¿At StemCells, it¿s liver stem cells, a lot on brain stem cells, and moving toward pancreatic islet stem cells. This work, I think, does not impact what¿s going on with those companies today. And I have an agreement with Stanford and with those companies that I did not inform the people at the company before the publication in Science of this research. We don¿t give any prepublic disclosure of research in my lab. Also, I don¿t tell my lab prepublic disclosures from the company. So it¿s hard to say how it would give the company an advantage, even if we had patented the work. Of course,¿ he concluded, ¿Stanford would put it up for grabs.¿

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