Cultivating Policy from Cell Types

For better or worse, stem cell science has become inextricably married to stem cell politics. Policymakers who oppose public financing of embryonic stem cells have used recent adult stem cell findings to argue for a dismissal of the NIH stem cell guidelines (see "On the Brink," page 1). The guidelines, finalized last summer during the Clinton administration, call for funding the use, but not derivation, of human embryonic stem cells (ESCs); the pro-life Bush administration appears ready to ban the funding of both. Yet many stem cell investigators insist that adult stem cell research does not preclude the need to study human ESCs, and that investigating both areas will allow for a cross-fertilization of ideas and techniques.1 "I don't think you could find anybody in this field who thinks you should abandon stem cell or embryonic research--yet," comments adult stem cell researcher Diane Krause, an assistant professor of laboratory medicine and pathology at the Yale University School of Medicine. "We all agree that we'd rather not have to deal with the ethical quagmire. But at this point we'll just be hurting our ability to progress if we stop the research." "There will be questions you can address with adult stem cells, and questions you address with ES cells. They complement each other," says James Thomson, a developmental biologist at the University of Wisconsin, Madison and the leader of one of two groups who were the first to culture human ESCs.2 "And, if you do both, both fields will actually go much faster." Right now, says Thomson, the adult versus embryonic stem cell "debate" is political rather than scientific. He likens the comparison to developmental biologists favoring the study of Drosophila over Caenorhabditis elegans--arguing which is better makes no sense; they're both useful for different reasons. Theoretically, ESCs are more plastic, while, at the moment, adult stem cells appear closer to proving more therapeutically valuable. Mark Pittenger, director of discovery research at Baltimore-based Osiris Therapeutics, which focuses on adult stem cells, encourages ESC research but feels that the company's adult stem cells "are going to be more useful." (see "The Potential of Human Mesenchymal Stem Cells," page 19). Embryonic stem cells, he points out, have many problems. It is more difficult, for example, to consistently get ESCs to differentiate into a given cell type. Adult stem cells are turning up in tissues throughout the human body, and they continue to defy initial expectations regarding both their plasticity and their utility. The stem cell potential of bone marrow cells has been known for decades. In the last few years, human skin and neural stem cells have been successfully cultured. And in the last few months, preliminary studies have indicated that adipose and placental tissues might harbor stem cells as well. "The cells ... residing in these tissues heretofore completely escaped detection mainly because nobody was looking for them," says Don Orlic, a stem cell researcher and staff scientist at the National Human Genome Research Institute. "Now all the activity is to try to identify sources of stem cells in various tissues and test them to see what they are capable of." Tickled by the possibility of harvesting cells of weighty potential from love handles and pudgy thighs, the media swarmed all over a recent paper reporting that stem cells might be derived from adipose tissue.3 Those responsible for the study, a team from the University of California, Los Angeles, knew when the research started four years ago of the existence of preadipocytes, fibroblast-like cells that can turn into mature adipocytes. Courtesy of Jane Ades, NHGRIScientists at the NIH and New York Medical College recently reported the best success to date using stem cells to treat heart attack damage in mice. "In looking at those cells, we noticed that there was spontaneous differentiation," says senior author Marc Hedrick, an assistant professor of surgery and pediatrics at UCLA. "Things sort of developed from there." As is common with stem cell research, the investigators had trouble definitively confirming that the cells identified were stem cells. But Hedrick claims that work done since the paper's submission has shown that the cells can divide in culture and maintain their ability to differentiate. "I feel comfortable now saying that these are indeed stem cells," he comments. But, even if they are indeed stem cells, they may not necessarily come from adipose tissue. "I tend to think that what we're really dealing with is pluripotent stem cells that circulate all the time and find their way to resting places among other tissues," says Richard D. Huhn, director of the umbilical cord stem cell laboratory at the Coriell Institute for medical research in Camden, N.J. (See also "Coriell Extends Its Scope," page 1). Huhn suggests that the fat cells may not have been turned into blood, but rather that investigators had accidentally detected blood cells among the fat cells. Probing Placenta Unpublished work from Anthrogenesis Corp. in Cedar Knolls, N.J., suggests that cells in human placenta could also give rise to stem cells. The company started this work three years ago, when it adapted its method of harvesting umbilical cord blood cells to reaping placenta. "Our technique essentially puts the placenta on a form of life support," says Anthrogenesis CEO Robert Hariri. For hours or days, the company feeds the placenta with the right nutrients and provides the physiological conditions to coax stem cell growth. Anthrogenesis says that the placental stem cells can produce cell types that derive from mesenchymal (marrow stromal) cells (bone, cartilage, tendon, ligaments, and muscle); they also yield neural and vascular cells. As with fat stem cells, clearly identifying the harvested cells as stem cells is an issue; some scientists suggest that Anthrogenesis investigators actually detected blood or other marrow-like stem cells. But Hariri suggests that the misleading detection of nonplacenta blood stem cells is unlikely since all blood is removed from the placenta prior to cell cultivation. His team tested for several hematopoietic markers to show that they had produced stem cells from placenta and not blood. Anthrogenesis plans to publish its findings once research methodology patents have been approved, Hariri says. Thomson and Orlic declined to comment on the findings' validity because they're unpublished. Huhn cautions that harvesting from placenta, while intriguing, has caveats; some placental cells can give rise to malignant cells. Transplanted cells wouldn't cause cancer, says Huhn, but they might be "very unusual in their differentiation and proliferation characteristics." Says Hariri, "The placenta is a source of cells in our system that is abundant, renewable, and economical. Our main objective is to ensure that scientists aren't limited in this research because of ethical concerns." Unprecedented Adult Potential Despite apparent new sources of adult stem cells, research involving bone marrow-derived mesenchymal stem cells (MSCs) remains the most common and potentially therapeutic. One recent mouse study reported promising results on adult stem cell-assisted repair of damaged heart tissue.4 A team lead by the NHGRI's Orlic and his collaborator Piero Anversa, a professor of medicine and director of the Cardiovascular Research Institute at New York Medical College, induced myocardial infarcts in mice. They not only showed that injected bone marrow cells can form myocytes and new blood vessels, but that the regenerated myocardial tissue partially restored lost heart function. Of the 30 treated mice, 12 regained function. Orlic speculates that the other 18 did not receive adequate numbers of cells because a mouse's physical attributes made the procedure difficult; mice have small hearts, thin ventricle walls, and a heart that beats 600 times per minute. (The human heart beats about 70 times per minute.) Although researchers presume that the cells responsible for yielding the beneficial cell types are bone-derived hematopoietic stem cells, Orlic admits that they still don't definitively know the cells' identity. Once they do, they can begin to investigate the molecular controls responsible for the bone marrow cells' migration into injured myocardium and their differentiation into myocardial cells. One possible way to discover whether hematopoietic stem cells are "doing the work" in myocardial regeneration is through gene marking studies. Gene insertion sites can be used to resolve questions of clonality, Orlic says. The group now plans long-term studies in adult mice. In hopes of working toward clinical trials, they also plan on doing similar studies in adult rhesus monkeys. The ultimate goal in humans is to inject stem cells into patients who'd recently suffered heart attacks. Last month, researchers at Yale and Johns Hopkins University reported an unprecedented level of plasticity in bone marrow-derived stem cells.5 In mice, they showed in vivo that a subpopulation of MSCs could create new liver, lung, gastrointestinal, and skin cells. As is done in standard bone marrow transplants, researchers irradiated recipient mice to destroy endogenous bone marrow. Then, they intravenously transplanted donor cells to the recipients--specifically, from male mice to female recipients. They tracked the donor cells by looking for the Y chromosome. They then discovered that just one cell type could produce not only male-derived blood--not a surprise since hematopoietic cells are known to be in the marrow--but also male-derived liver, lung, GI tract, and skin. "We're showing that adult-derived bone marrow cells have a huge amount of plasticity, more than we ever thought possible," says Krause, lead author. "But we have not at this point shown that they have the same amount of plasticity as an embryonic stem cell or a fetal derived cell and we do not feel that at this stage that embryonic stem cell research should be abandoned. And we don't want our data used to support that argument." In the area of diabetes research, the applications of ESCs have made a clear contribution beyond the known abilities of adult stem cells. In late April, scientists at the National Institute of Neurological Disorders and Stroke reported using embryonic stem cells to not only make insulin-secreting cells, which had been done previously,6 but "mini-organs" in which the whole insulin-producing islet assembles in vitro with other types of islet-specific cell types.7 Another group had previously used adult stem cells derived from the pancreatic duct to generate insulin-producing cells,8 but did not assemble a functional "mini-organ" as did the NINDS group. Krause calls the diabetes research a "wonderful argument" for why embryonic stem cell research must continue. "We had an old paradigm that said once you were an adult, there were only tissue-specific stem cells .... And basically we've proved that paradigm wrong. We should keep our minds open to all of these possibilities." Eugene Russo can be contacted at erusso@the-scientist.com.Ricki Lewis (rickilewis@nasw.org) also contributed to this article. References 1. D. Steinberg, "Stem cell discoveries stir debate," The Scientist 14[22]:1, Nov. 13, 2000. 2. R. Lewis, "Embryonic stem cells debut amid little media attention," The Scientist, 11[19]:1, Sept. 29, 1997. 3. P.A. Zuk et al., "Multilineage cells from human adipose tissue: implications for cell-based therapies," Tissue Engineering, 7:211-28, April 2001. 4. D. Orlic et al., "Bone marrow cells regenerate infarcted myocardium," Nature, 410:701-5, April 5, 2001. 5. D.S. Krause et al., "Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell," Cell, 105:369-77, May 4, 2001. 6. B. Soria et al., "Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice," Diabetes, 49:157-62, 2000. 7. N. Lumelsky et al., "Differentiation of Embryonic Stem Cells to Insulin-Secreting Structures Similar to Pancreatic Islets," Science, on the Web at www.sciencemag.org/sciencexpress/recent.shtml, scroll to April 26, 2001. 8. V.K. Ramiya et al., "Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells," Nature Medicine, 6:278-82, March 2000.

Cultivating Policy from Cell Types

Interested in reading more?

Become a Member of