Stem Cell Potential Grows

A number of recent publications have added to scientists' understanding of embryonic stem cell (ESC) differentiation and adult stem cell plasticity. For example, Ron McKay and coworkers at the National Institute of Neurological Disorders and Stroke, demonstrated that they can direct murine ESCs to differentiate into a particular type of dopamine-producing neuron, which could aid in the treatment of Parkinson disease. 1 Transplantation of stem cell precursors derived from the fetal midbrain leads to functional recovery in animal models of Parkinson, explains McKay, but researchers' ability to grow these cells in the laboratory is limited. "A solution to that problem would be to start with the embryonic stem cell, because [it] can essentially be expanded in the lab without limit," says McKay. "If you could get the right kind of dopamine neuron from an embryonic stem cell, ... it would show for the first time that you could really use stem cell technology in Parkinson's disease research." McKay's group introduced a gene for Nuclear receptor related-1 (Nurr1), a transcription factor necessary for the differentiation of precursor cells into dopamine neurons, into murine ESCs. They then grafted these cells into rat brains that were modified to mimic Parkinson symptoms. Behavioral, electrophysiological, and anatomical tests revealed recovery of brain function in the animals receiving the ESC grafts. The paper is the first to demonstrate that cell differentiation can be controlled in the laboratory at all stages of development, from ESCs to fully functional adult neurons, says McKay. "In principle, of course, embryonic stem cells can make every cell in the body, so to show that they can make some kind of differentiated cell, while it's interesting, is not really that surprising. But to show that you can control it, that's very important," McKay explains. Further, the paper demonstrates ESCs' potential in cell therapy. "It's one of the first papers illustrating actual functional recovery after ESC-derived injections in vivo," says Gwenn-aël Danet, research associate, University of Pennsylvania. In a later publication, researchers at Columbia University demonstrated directed differentiation of mouse ESCs into spinal progenitor cells and motor neurons. 2 McKay explains that scientists working with ESCs have an advantage over those working with adult stem cells: They can use their understanding of normal developmental patterns as a guide in developing strategies for controlled differentiation. "The methods we used in this paper ... take advantage of what we know of the normal patterns of development," McKay says. "It might take us quite a while to figure out how to work with adult [stem] cells." Nevertheless, scientists' understanding of the plasticity and potential of adult stem cells has sharply increased in the past year, leading some to speculate that pluripotent adult stem cells may exist. "People are starting to think that, especially in bone marrow, you might keep a population of truly pluripotent cells. There's a big push to see how far they can take adult hematopoietic stem cells and cause them to differentiate into a broad range of tissue types--nerve, gut, skin, you name it," says M. Celeste Simon, associate professor, Department of Cell and Developmental Biology , University of Pennsylvania. For example, last year Diane Krause of Yale University, and colleagues described the colonization of multiple tissues by a single adult bone marrow-derived stem cell. 3 Surprisingly, they found that hematopoietic stem cells can differentiate into hematopoietic as well as epithelial cells in mouse models; and, as a result, can potentially be used to repopulate injured or diseased organs in a variety of tissues. More recently, Catherine Verfaillie and colleagues at the University of Minnesota School of Medicine demonstrated similar results with a single cell from a class of bone marrow-derived stem cells termed MAPCs, for multipotent adult progenitor cells. MAPCs are unique in that they can be expanded in culture more than 100 times without differentiation, unlike most adult stem cells, which can not be continuously expanded. Verfaillie's group injected MAPCs into early mouse blastocysts and found that up to 45% of the cells in the tissues of the chimeric mice were donor-derived. 4 MAPCs differentiated into endodermal and epithelial cells as well as mesenchymal cells and were represented in all organs with the exception of cardiac and skeletal muscular tissue. Most studies of adult stem cell plasticity have used mouse models, as such studies are significantly more challenging for human cells. "The absence of an animal model for the study of human stem cell plasticity has been a serious limitation. It's not always convenient to have to go back to biopsies and historical tissue banks of transplanted people to look for donor-derived cells," says Danet. In a new article, Danet and colleagues overcame these problems using immune-deficient mice, which were injected with human adult stem cells derived from bone marrow or cord blood. 5 Various tissues were then screened for the presence of cells derived from the donor and the scientists found that human donor cells repopulated both the bone marrow and liver tissue of recipient mice. References 1. J.-H. Kim et al., "Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease," Nature, 418:50-6, July 4, 2002. 2. H. Wichterle et al., "Directed differentiation of embryonic stem cells into motor neurons," Cell, 110:385-97, August 9, 2002. 3. D.S. Krause et al., "Multi-organ, multi-lineage engraftment by a single bone-marrow derived stem cell," Cell, 105:369-77, 2001. 4. Y. Jiang et al., "Pluripotency of mesenchymal stem cells derived from adult marrow," Nature, 418:41-9, July 4, 2002. 5. G.H. Danet et al., "C1qRp defines a new human stem cell population with hematopoietic and hepatic potential," Proceedings of the National Academy of Sciences, 99:10441-5, Aug. 6, 2002.

Stem Cell Potential Grows

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Aileen Constans

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September 2002

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