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The Scientist 14[23]:20, Nov. 27, 2000 http://www.thescientist.com/yr2000/nov/research_001127.html Blood Goal: To develop a limitless source of blood cells for transfusions. Over the past 30 years, a small army of researchers has investigated the culture conditions under which hematopoietic ASCs preferentially give rise to myeloid or lymphoid lineages. (Relatively pure cultures of red blood cells have been the most elusive to produce.) Gordon Keller, a professor at Mount Sinai School of Medicine's Institute for Gene Therapy and Molecular Medicine, has succeeded at differentiating mouse ESCs into a variety of blood cell types, though he admits that generating lymphocytes is still a problem. His lab has developed the requisite protocols by trial and error over the past decade.19 When removed from conditions that keep them in an undifferentiated state, ESCs form clusters of differentiating cells called embryoid bodies. "At that point, we take the cells from the embryoid body and put them into cultures containing cytokines that stimulate the growth and maturation of blood-cell progenitors," Keller recounts. "Alternatively, we can first isolate the blood-cell progenitors from the embryoid bodies by using antibodies to specific cell-surface markers and then put them into culture." Keller is now searching within embryoid bodies for the hematopoietic stem cell equivalent to the hematopoietic ASC that other labs have isolated in bone marrow. This putative stem cell in the embryoid body has been harder to find, he says, because it "appears to be more immature than the one in adult bone marrow." His approach is to transplant candidate stem cells into mice with drug-damaged hematopoietic systems and then to observe whether blood-cell re-population occurs. When might his methods boost human blood supplies for transfusions? "Some years away" is all that Keller will predict. Douglas Steinberg is a freelance writer in New York. References 1. D. Steinberg, "Stem cell discoveries stir debate," The Scientist, 14[22]:1,14-5, Nov. 13, 2000. 2. S.-H. Lee et al., "Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells," Nature Biotechnology, 18:675-9, June 2000. 3. L. Studer et al., "Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats," Nature Neuroscience, 1:290-5, 1998. 4. L. Studer et al., "Enhanced proliferation, survival, and dopaminergic differentiation of CNS precursors in lowered oxygen," Journal of Neuroscience, 20:7377-83, Oct. 1, 2000. 5. J. Wagner et al., "Induction of a midbrain dopaminergic phenotype in Nurr1-overexpressing neural stem cells by type 1 astrocytes," Nature Biotechnology, 17:653-9, 1999. 6. C.B. Johansson et al., "Identification of a neural stem cell in the adult mammalian central nervous system," Cell, 96:25-34, 1999. 7. F. Doetsch et al., "Subventricular zone astrocytes are neural stem cells in the adult mammalian brain," Cell, 97:703-16, 1999. 8. N. Wade, "Brain stem cell is discovered, twice," New York Times, p. F3, June 15, 1999. 9. One paper is in press. For the other, see J.C. Conover et al., "Disruption of Eph/ephrin signaling affects migration and proliferation in the adult subventricular zone," Nature Neuroscience, 3:1091-7, November 2000. 10. D.L. Clarke et al., "Generalized potential of adult neural stem cells," Science, 288:1660-3, June 2, 2000. 11. B.J. Chiasson et al., "Adult mammalian forebrain ependymal and subependymal cells demonstrate proliferative potential, but only subependymal cells have neural stem cell characteristics," Journal of Neuroscience, 19:4462-71, 1999. 12. E.D. Laywell et al, "Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain," Proceedings of the National Academy of Sciences (PNAS), in press. 13. B. Soria et al., "Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice," Diabetes, 49:157-62, February 2000. 14. 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. 15. S. Bonner-Weir et al., "In vitro cultivation of human islets from expanded ductal tissue," PNAS, 97:7999-8004, July 5, 2000. 16. N.D. Theise et al., "Liver from bone marrow in humans," Hepatology, 32:11-6, July 2000. 17. E. Lagasse et al., "Purified hematopoietic stem cells can differentiate into hepatocytes in vivo," Nature Medicine, 6:1229-34, November 2000. 18. M.G. Klug et al., "Genetically selected cardiomyocytes from differentiating embryonic stem cells form stable intracardiac grafts," Journal of Clinical Investigation, 98:216-24, 1996. 19. See, e.g., M. Kennedy et al., "A common precursor for primitive erythropoiesis and definitive haematopoiesis," Nature, 386:488-93, 1997. *************************