The Potential of Human Mesenchymal Stem Cells

For this article, Eugene Russo interviewed Mark F. Pittenger, director of discovery research at Osiris Therapeutics. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. M.F. Pittenger, A.M. Mackay, S.C. Beck, R.K. Jaiswal, R. Douglas, J.D. Mosca, M.A. Moorman, D.W. Simonetti, S. Craig, D.R. Marshak, "Multilineage potential of adult human mesenchymal stem cells," Science, 284:143-7, April 2, 1999. (Cited in 145 papers) Mark F. Pittenger (left), Alastair Mackay (right) In 1999, investigators at Osiris Therapeutics in Baltimore arguably accomplished a major first in stem cell research. Using the right recipe of experimental ingredients and conditions, they coaxed human bone marrow cells into three separate cell lineages.1 "A bunch of people said, 'Oh, this had been done before,'" comments lead author Mark F. Pittenger. "People had previously grown cells out of marrow for different purposes, but it was not clear [until Osiris' work] that results showing different lineages were due to a single cell type rather than multiple cell types." While scientists have known for 35 years that cells found in bone marrow can form different tissues,2,3 not until 1992 had researchers isolated this cell population from human tissue.4 It was careful cell characterization, careful in vitro assays, and careful clonal analysis that contributed to the paper's impact, suggests Pittenger, who is now Osiris' director of discovery research. These elements together, he says, demonstrated that human mesenchymal stem cells (hMSCs) could be derived from bone marrow cells. Osiris investigators achieved differentiation into adipocytes (fat cells), chondrocytes (cartilage cells), and osteocytes (bone cells). Initially, his group sought to generate in vitro assays that would be helpful in understanding cellular differentiation. "We went through a lot of literature, we tried a lot of different methods for differentiating the cells," he explains. "Some worked, some didn't." Then, through trial and error, they found the right combination of hormones, growth factors, vitamins, and serum and the correct methods to get the hMSCs to differentiate into each lineage. For example, to achieve adipocytic differentiation, the cells had to be confluent; whereas, too high a cellular density actually inhibited osteocytic differentiation. "The cells are responding to signals we still don't fully understand," Pittenger comments. After an initial read, Science reviewers liked what they saw but wanted clonal data. The Osiris team spent weeks expanding the hMSCs to prove that the cells could still differentiate after more than 20 population doublings, but some stopped growing. It's still not clear, says Pittenger, whether these stymied cells had undergone too many population doublings or whether the lab's in vitro conditions weren't perfect--questions he'd like to answer. According to Pittenger, each lineage represents a large market of therapeutic products for Osiris. This summer, the company plans to enter phase III trials to use hMSCs in breast cancer and bone marrow transplant patients undergoing chemotherapy. The hMSCs appear to help hematopoietic stem cells engraft more quickly, and, as a result, help patients achieve a quicker recovery. Osiris has tried similar strategies with lymphoma with some success. They've also been looking into generating cardiomyocytes from their hMSCs, a feat that recently showed promise in treating heart attack damage in mice.5 Pittenger says that his team is intent on "progressing towards a real product," something he doesn't think is that far off. Pittenger admits that being one of the first companies to enter the tricky area of stem cell research has led to moments of self-doubt. "When I joined the company in 1994, the prospects that you could have a single cell that could go down this many lineages was pretty far-fetched," says Pittenger. Thus far, he and his colleagues have been "pleasantly surprised by the cells." Eugene Russo can be contacted at erusso@the-scientist.com References 1. R. Lewis, "Human Mesenchymal Stem Cells Differentiate in the Lab," The Scientist, 13[8]:1, April 12, 1999. 2. A.J. Friedenstein et al., "Osteogenesis in transplants of bone marrow cells," Journal of Embryology and Experimental Morphology, 16:381-7, Part 3 1966. 3. M. Owen, A.J. Friedenstein, "Stromal stem-cells - marrow-derived osteogenic precursors," Ciba Foundation Symposia, 136:42-60 1988. 4. S.E. Haynesworth et al., "Characterization of cells with osteogenic potential from human bone marrow," Bone, 13:81-88, 1992. 5. D. Orlic et al., "Bone marrow cells regenerate infarcted myocardium," Nature 410:701-5, April 5, 2001.

The Potential of Human Mesenchymal Stem Cells

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