By David N. Leff

It will take years, but human embryonic stem cells are starting to blaze a trail to the pot of therapeutic gold at the end of the rainbow.

That pot is already beginning to fill up with human blood cells, as reported by developmental biologist James Thomson, at the University of Wisconsin in Madison. He is the scientist who pioneered the isolation and culture of human embryonic stem cells, three years ago. (See BioWorld Today, Nov. 6, 1998, p. 1.)

Thomson is senior author of a just-published paper in the Proceedings of the National Academy of Sciences (PNAS), dated Sept. 11, 2001, but released electronically Sept. 3. Its title: ¿Hematopoietic colony-forming cells derived from human embryonic stem cells [hES].¿ Its first author is clinical hematologist Dan Kaufman, a research fellow collaborating with Thomson.

¿For the first time,¿ he and his co-authors state, ¿we have demonstrated that undifferentiated human embryonic stem cells can be teased down a developmental pathway to become blood cells. These results,¿ Kaufman added, ¿show an effective and efficient way to derive blood cells from these early precursors.¿

¿The team derived their blood cell lines from the original five embryonic stem cell lines that Thomson established in 1998. Those preimplantation embryonic stem cell lines came from the university hospital¿s in vitro fertilization clinic, and from scientists in Israel,¿ the university¿s , Terry DeVitt, told BioWorld Today. They retained their pluripotent potential of differentiating into any of the 220 types of cells and tissues that make up the human body.

¿The ability to create unlimited supplies of human blood in the lab,¿ Kaufman observed, ¿has obvious implications for augmenting donor blood supplies for transfusion and for transplant therapies to treat cancers of the blood and bone marrow, such as leukemias and myelomas.¿

But mice are still in the hES cell picture. The Wisconsin researchers grew their human embryonic stem cells in culture together with murine bone marrow or yolk sac cell lines ¿ factors that promote blood-cell development.

From Single Cell To Full Blood Components

Thus guided and prodded along the blood-forming pathway, the hES cells first turned into primitive hematopoietic precursor cells. These went on to form colonies of white blood cells, red cells and platelets ¿ identical to those produced from human adult bone-marrow cells. More terminally differentiated hematopoietic cells derived from the hES cells also expressed normal surface antigens: glycophorin A (which occurs on red blood cell membranes), CD15 (expressed in patients with Hodgkin¿s disease and leukemias) and CD41 (found on megakaryocytes, which give rise to platelets). ¿Here, we show,¿ the PNAS paper concluded, ¿that coculture of human ES cells with certain stromal cell lines derived from mouse hematopoietic tissue leads to differentiation into hematopoietic cells.¿

¿Finding out how to direct differentiation of embryonic stem cells,¿ Kaufman pointed out, ¿blank-slate cells that arise at the earliest stages of development, to become blood, bone, skin, nerve and other cell types, is one of the biggest technical challenges facing scientists as they work to advance stem cell technology. This is not something that¿s going to be available tomorrow or next year,¿ he went on, ¿but the research does represent a key step forward in the quest to direct a stem cell to become a specific cell type.¿

He made the point, ¿The need for certain kinds of blood cells for transplant is acute. Only about 25 percent of patients who need blood or bone-marrow transplants from a donor person to treat leukemias and other cancers get those transplants,¿ for lack of immune compatibility. ¿A goal,¿ he added, ¿would be to better treat those remaining 75 percent with well-matched donor cells.¿

¿Human ES cells provide a unique, homogeneous, unlimited starting population of cells for studying human hematopoiesis,¿ the PNAS paper pointed out. ¿They can be cultured for at least 300 population doubling times without observing senescence, while continuing to maintain normal karyotypes, telomere lengths and pluripotency. Moreover, these cells can be cloned from a single cell without loss of pluripotency.¿

The paper suggested that hematopoietic precursor cells derived from hES cells could, potentially, be genetically modified to treat specific patients or combat specific diseases. They may also provide a powerful method of preventing immune rejection of transplanted grafts by creating tolerance to other embryonic stem cell-derived tissues that share the same genetic background.

Some 20,000 bone-marrow transplants are conducted annually in the U.S. to treat leukemias and other diseases. In humans and other animals, blood is constantly renewed in bone marrow, and marrow transplants have proved effective in treating blood and bone cancers.

¿ES cell-derived hematopoietic stem cells [HSC] could dramatically increase both the availability and the effectiveness of HSC transplantation for the treatment of hematologic malignancies,¿ the paper noted. ¿By using human ES cells as the starting cell population, a sufficiently large dose of pure HSCs could be generated which would permit allogeneic [within-species] engraftment.¿

Clinical Applications Unlimited, Years Off

Thomson made the added point that ¿the derivation of engraftable HSCs from human ES cells will have implications for human medicine far beyond the treatment of hematologic malignancies, as these HSCs may provide a powerful method to prevent immune rejection of other ES cell-derived tissues.¿ But he also raised a caveat: ¿The clinical promise of human ES cell-based therapies is great; however, because these therapies will be entirely novel, serious concerns about safety and efficacy will need to be addressed before human clinical trials can be initiated. The malignant transformation of cells that have been cultured for extended periods is a particular concern.¿

Thomson is associated with the university¿s Regional Primate Research Center. He addressed this concern by concluding: ¿We have very recently isolated ES cells from rhesus monkeys, and demonstrated their hematopoietic potential. It will be possible to use those primate cells as an accurate, preclinical transplantation model for human ES cell-based therapies.¿

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