University of Minnesota stem cell researchers, together with collaborators at Stanford University, have successfully used adult stem cells to replace the immune system and bone marrow of mice, offering the promise of new therapies for people in the future. With this advance and other recent discoveries, the researchers are winning over previous skeptics.

For decades, researchers have tried in the lab to expand hematopoietic stem cells (cells that give rise to the blood system). Success in this venture would mean increasing the supply of cells available for bone marrow transplant patients. The researchers used multipotent adult progenitor cells (MAPCs), which can be isolated from bone marrow and have the ability in the laboratory to differentiate into different specific types of cells such as liver, bone and neural cells.

Catherine Verfaillie, M.D., director of the University’s Stem Cell Institute, first identified MAPCs in 2001. Since then, many in the scientific community have been skeptical of their existence and their functioning as Verfaillie has described. This skepticism mostly arose due to difficulty in reliably growing these cells, which made reproduction in other labs problematic. Since their identification, the methods to isolate and grow MAPCs have been improved (see publication in Experimental Hematology, October 2006). This latest research will be available online from the Journal of Experimental Medicine on January 15; it will appear in the Jan. 22, 2007; print edition of the journal.

Verfaillie and her team isolated MAPCs from mice and expanded them for at least 80 doublings in the lab. They then transplanted the cells into mice that received radiation and thus had no immune system.

“The cells not only survived when transplanted but they completely repopulated the blood system of the mice,” Verfaillie said. The MAPCs did not differentiate into other cell types, such as liver or brain cells, nor did they form tumors in any animals.

Irving Weissman, M.D., Stanford University professor of pathology and developmental biology and co-author on the manuscript, was admittedly skeptical at first about the ability of MAPCs to contribute to blood formation. This skepticism made him an ideal collaborator, as he insisted on rigorous evaluation of the data. “These experiments point to potential precursors of blood forming stem cells in an unexpected population of cultured cells,” said Weissman, who directs Stanford’s Institute for Stem Cell Biology and Regenerative Medicine.

“Scientists must now understand that mouse MAPCs can make normal blood, and we need to explore how they do it,” Weissman said. “It is very important to note that MAPCs were not themselves radioprotective, thus they alone could not be used in patients in whom the bone marrow is totally eliminated due to radiation or chemotherapy, but it is still remarkable that they can give rise to blood cells.”

Bruce Blazar, M.D., professor of Pediatrics at the University of Minnesota, who is co-author of the paper, has continued with experiments conducted in his laboratory after the completion of this study. “Our results independently confirmed in an additional series of animals the finding that MAPCs can make blood cells,” Blazar said. While more research will need to be done and studies need to be replicated with human MAPCs before human treatments are available, this research suggests that MAPCs could be used to help reduce rejection of tissue transplants. In the future, physicians may be able to introduce MAPCs in the blood system of the recipient to trick the immune system into accepting the MAPC-generated transplanted tissue. In addition to this paper, in the last few months further evidence of MAPCs existence and function was published in scientific peer-reviewed journals based on research done at the University and other research institutions across the world. “I am pleased to see this science replicated at other research universities,” Verfaillie said. “Now there is further confirmation that the MAPCs could be a valid source of new therapies.” Verfaillie added this research shows the importance of continuing to pursue all types of stem cell research, adult and embryonic, because scientists do not yet know which cell type will prove most promising for treating a particular disease.

MAPCs found in pigs

Verfaillie and colleagues had previously isolated MAPCs from bone marrow of humans, mice and rats. But in order to study potential treatments for people, the research needs to be tested in animal models that are more physiologically similar to humans. In the November 2006 issue of the journal Stem Cells, Verfaillie described how MAPCs can be isolated from pig bone marrow. Pigs are routinely used as a model for humans, especially in cardiovascular research. The researchers were able to isolate and grow the pig MAPCs with some modifications much like they identify human, mouse and rat MAPCs. After isolating the MAPCs, the scientists were able to differentiate the cells into different types of cells that give rise to bone, smooth muscle, fat, cartilage, endothelium (cells that line blood vessels), and cells that are similar to liver and brain cells.

MAPCs and endothelial cells

A team of researchers from the University of Navarra in Pamplona, Spain, the Catholic University of Leuven, Belgium, and the University of Minnesota published in the journal Blood (November 2006) on the ability of MAPCs to differentiate into two types of endothelial cells, which line the inner walls of blood vessels. By adding various growth factors, the researchers, led by Felipe Prosper, M.D., of Spain, were able to make the human MAPCs differentiate into both arterial endothelial and venous endothelial cells in both a laboratory environment and in mice. Like the studies showing that MAPCs can make blood when transplanted, this is a second example demonstrating that MAPCs can contribute to a tissue when grafted in vivo. “This work provides the first evidence that human MAPCs can be induced to differentiate into the different types of cells needed to form arteries,” Prosper said. “This may suggest future clinical applications for MAPCs in diseases and conditions such as stroke and heart attack.” In addition, this discovery provides researchers a model to study how human arteries and veins develop.

MAPCs create smooth muscle

Verfaillie and colleagues published in the December 2006 issue of the Journal of Clinical Investigation that MAPCs can generate smooth muscle cells in the laboratory. Smooth muscle cells contract, often without conscious control, regulating body functions such as blood pressure and movement of food through the digestive system.

“While previous research has demonstrated that various types of stem cells can turn into cells that express the proteins consistent with smooth muscle, this is the first study that shows that the cells we generated have the same functional properties as smooth muscle, as well as express the same proteins,” said Jeffrey Ross, Ph.D., research associate at the Stem Cell Institute. These observations suggests that in the future, researchers may be able to make functional tissue in the lab from MAPCs, such as engineering a new blood vessel for use in bypass surgery. As smooth muscle cells are involved in many diseases like hypertension or asthma, the ability to generate smooth muscle cells with all functional attributes of this cell type also opens the possibility that they can be used to screen new drugs in the lab to determine how the cells react to potential new therapies.

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Contact: Sara E. Buss

University of Minnesota