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Weill Cornell Scientists Unlock Mechanism for Recovering Autologous Adult Bone Marrow Stem Cells for Tissue Regeneration

Alternative Source of Dispensable Adult Stem Cells May Be Used Instead of Problematic Embryonic Stem Cells

Ethical Issues of Embryonic Stem Cells Circumvented

NEW YORK (May 28, 2002)

Scientists from Weill Medical College of Cornell University have discovered the mechanism by which a renewable source of autologous organ-specific adult bone marrow stem cells may be recruited. While embryonic stem cells—that is, stem cells derived from embryos—have been the subject of much recent attention and ethical debate, stem cells derived from adult bone marrow may prove to be even more suitable for therapeutic purposes, both as the key to blood vessel formation (angiogenesis) in tumors and as an alternative source of replaceable stem cells that can be used readily for fighting disease through organ regeneration and gene therapy.

The use of organ-specific stem cells from adult bone marrow has long been hampered because of the lack of knowledge regarding the mechanism by which these scarce populations of stem cells—which normally hibernate in the safe haven of the bone marrow—proliferate, self-renew, and are recruited to be mobilized to the peripheral blood, where they incorporate into damaged tissue.

Leading the research into harnessing the adult bone marrow stem cells are Dr. Shahin Rafii and colleagues from Weill Cornell, who report findings with regard to the mechanism by which stem cells are stimulated to expand and release from bone marrow. Their research, published in the May 31 issue of Cell, provides enormous promise for the development of far-reaching therapeutics.

The newly unlocked mechanism may be the key for facilitating future treatments of countless diseases, ranging from heart disease and stroke to diabetes and Parkinson's.

Dr. Rafii emphasizes that adult bone-marrow-derived stem cells are not entangled in any of the ethical debates that have made the use of embryonic stem cells problematic. By stimulating the production of autologous stem cells from the adult bone marrow, thereby facilitating their recovery, doctors may eventually be able to restore the functioning of diseased mature organs such as the heart, muscle, lung, kidneys, pancreas, and brain.

Not only ethically but also for therapeutic purposes, Dr. Rafii says, autologous adult bone-marrow-derived stem cells may have an advantage over embryonic stem cells in that they possess "the appropriate developmental instructions and are more likely to engraft functionally into an adult tissue, undergoing regeneration during development or after injury."

Dr. Rafii and colleagues—Drs. Beate Heissig and Koichi Hattori (both also of Weill Cornell's Division of Hematology-Oncology)—detail the involvement of an enzyme, metalloproteinase-9 (MMP-9), and a stem-cell-active cytokine, Kit-ligand (also known as Stem Cell Factor), in the production and mobilization of bone marrow stem cells. To put it simply, physiological stress, as may occur during tissue injury, activates MMP-9 in bone marrow cells, and that promotes the release of Kit-ligand, which leads to the proliferation and mobilization of stem cells from a dormant microenvironment of the bone marrow to an environment that promotes their expansion, differentiation, and mobilization to the bloodstream.

Another collaborator in this project, Dr. Zena Werb, from the University of California at San Francisco, has previously shown that the MMP-9 plays a major role in bone formation. Dr. Werb generated genetically engineered mice that lacked the capability of expressing MMP-9. In the new study, Dr. Rafii and colleagues found that bone-marrow-derived stem cells of MMP-9-deficient mice failed to regenerate after the mice were treated with chemotherapeutic marrow-suppressive agents. Compared to the control wild-type mice, almost 70% of the MMP-9-deficient mice died from complications of bone-marrow suppression due to failure of stem cell proliferation, leading to life-threatening hemorrhage and infection.

The conclusion was that activation of MMP-9 is essential for release of stem-cell-active cytokines, including Kit-ligand, which promote the reconstitution of blood and vascular and blood-generating stem cells. This cascade of events leads to significant expansion of stem cells that move in large numbers to the peripheral circulation, facilitating recovery for future use.

These exciting results lay the foundation for developing strategies whereby activation of enzymes such as MMP-9 or other as-yet-unrecognized organ-specific proteases can function as molecular switches to expand and recover a large population of autologous hibernating stem cells for use in tissue-regeneration and gene therapy.

Last November, Dr. Rafii and Dr. David Lyden (another co-author of the present paper) reported in Nature Medicine that bone-marrow-derived vascular stem cells contribute to angiogenesis and growth of certain tumors. That article, by showing the involvement of bone marrow stem cells in tumor angiogenesis, pointed to novel strategies by which the growth of tumors might be reduced or reversed. Drs. Rafii and Lyden note that based on the knowledge gained from the present report in Cell, novel anti-cancer strategies might be designed whereby large numbers of autologous stem cells would be repeatedly harvested from patients with cancer, genetically modified to produce toxins, and then re-introduced—loaded with toxins—to be used as "biological cruise missiles" delivering the toxins to tumor vasculature.

Besides Drs. Rafii, Heissig, Hattori, Werb, and Lyden, the authors of the new article are Sergio Dias, Matthias Friedrich, Barbara Ferris, of Weill Cornell's Division of Hematology-Oncology; Neil R. Hackett and Ronald G. Crystal of Weill Cornell's Division of Genetic Medicine; and Peter Besmer and Malcolm A. S. Moore of the Sloan-Kettering Institute for Cancer Research.

The work was supported by grants from the National Institutes of Health, the Sandler Family Sustaining Foundation, the Doris Duke Charitable Foundation, the National Heart, Lung, and Blood Institute, the American Cancer Society, Leukemia and Lymphoma Foundation, and the Lupin Foundation.

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