Margaret A. Goodell, Ph.D.
Department of Pediatrics
Section of Hematology-Oncology
Baylor College of Medicine
- Ph.D., University of Cambridge, England
- Postdoctoral Fellow, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA
Hematopoietic Stem Cell Biology. We are interested in the basic biology of hematopoietic stem cells. It has been known for decades that hematopoietic stem cells reside in the bone marrow in a quiescent state and replenish the supply of differentiated cells of the peripheral blood throughout the lifetime of an animal. No other adult cell type retains the capacity for such immense proliferation and differentiation. However, little is known about the cells or factors that regulate their primitive state or control their activation.
We discovered a novel way to purify murine hematopoietic stem cells and can now obtain large numbers of highly purified stem cells in order to address some of these basic questions. We will study the behavior of these cells in vivo and in vitro, as well as pursue the mechanisms which control their behavior on a molecular level. The purification is based on the observation that the stem cells retain only small amounts of a fluorescent dye relative to other cells of the bone marrow after a simple staining procedure. We found that this is due to active efflux of the dye from stem cells by a multi-drug resistance-type transporter, the identity of which is presently unknown. It is likely that this transporter is involved in regulation of stem cell activity. We are also particularly interested in the mechanisms which govern the cell cycle status of the stem cells, as this may be the key to the ability to expand and manipulate the stem cells in vitro, which will ultimately assist our interests in gene therapy. Hematopoietic Stem Cell Gene Therapy: Hematopoietic stem cells have been of great interest for gene therapy due to the large number of diseases, both genetic and acquired, that potentially can be ameliorated via bone marrow stem cells. Although hematopoietic diseases have been the focus of some of the first gene therapy trials, and gene transfer has been demonstrated to occur and persist for up to 6 years, therapeutic benefit has been limited by the poor overall levels of gene transfer. We hope to find ways to improve the prospects for hematopoietic stem cell gene therapy.
A better understanding of human hematopoietic stem cells may be a first step. Through the application of our stem cell purification method to species other than mice, we found a population of cells in monkey, pig, and human bone marrow which may be a precursor to cells previously thought to be the most primitive cells in human bone marrow. If this is indeed the case, these may be superior targets for gene therapy. We are studying the hematopoietic potential of these cells in vitro and in vivo. In addition we will develop gene transfer methods for these cells to enable their study and clinical use.
- Goodell, M. A., Brose, K., Paradis, G., Conner, A. S., and R. C. Mulligan (1996) Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J. Exp. Med. 183: 1797-1806.
- Goodell, M. A., Rosenzweig, M., Kim, H., Marks, D. F., De Maria, M., Paradis, G., Grupp, S., Seiff, C. A., Mulligan, R. C., and R. P. Johnson (1997) Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nature Medicine. 3: 1337-1345.
- Jackson, K. A., Mi, T., and M. A. Goodell (1999) Hematopoietic Potential of Stem Cells Isolated from Murine Skeletal Muscle. PNAS. 96: 14482-14486.
- Jackson, K. A., Majka, S., Wang, H., Pocius, J., Hartley, C. J., Majesky, M. W., Entman, M. L., Michael, L. H., Hirschi, K. K., and M. A. Goodell (2001) Regeneration of Ischemic Cardiac Muscle and Vascular Endothelium by Adult Stem Cells. Journal of Clinical Investigation. 107: 1395-1402.
- Wulf, G. G., Wang, R.-Y., Kuehnle, I., Weidner, D., Marini, F., Brenner, M. K., Andreeff, M., and M. A. Goodell (2001) A leukemic stem cell with intrinsic drug efflux capacity in acute myeloid leukemia. Blood. 98: 1166-1173.
- McKinney-Freeman, S. L., Jackson, K. A., Camargo, F., Ferrari, G., Mavilio F., and M. A. Goodell (2002) Muscle-derived Hematopoietic Stem Cells are Hematopoietic in Origin. PNAS. 99:1341-1346.
- Welm, B.E., Tepera, S.B., Venezia, T., Graubert, T.A., Rosen, J.M., and M. A. Goodell (2002) Sca-1(pos) Cells in the Mouse Mammary Gland Represent an Enriched Progenitor Cell Population. Dev. Biol. 2002; 245:42-56.
- Castro, R.F., Jackson, K.A., Goodell, M.A., Robertson, C.S., Liu, H., and H. David Shine (2002) Failure of Bone Marrow Cells to Transdifferentiate into Neural Cells In Vivo. Science. 297; 1299.
- Wulf, G. G., Jackson, K. A., and M. A. Goodell (2001) Somatic Stem Cell Plasticity: Current Evidence and Emerging Concepts. Experimental Hematology. 29: 1361-1370.
- Goodell, M. A. (2001) Stem Cell Identification and Sorting Using the Hoeschst 33342 Side Population (SP). In Current Protocols in Cytometry (J. P. Robinson, Z. Darzynkiewicz, P. N. Dean, A. R. Hibbs, A. Orfao, P. S. Rabinovitch, and L. L. Wheeless, eds.) pp. 9.18.1-9.18.xx. John Wiley & Sons, New York.