Scadden David MD
Indeed, they are trying to solve three problems that limit the ability of stem cells to be used more effectively as therapy. The first is stem cell number. They are using a range of genetic and cell biologic approaches to understand the cell autonomous and extrinsic regulators of stem cell cycling and self-renewal. Specifically, their group uses both comparative genomics and shRNA forward screening to identify candidate mediators of the self-renewal program in hematopoietic stem cells. Second, they are studying stem cell localization as delivery of stem cells to specific sites is critical for their application clinically. They have identified novel mechanisms regulating the ability of the stem cell to engage its proper niche using genetic models and high resolution in vivo imaging. Third, they are deeply interested in viewing the stem cell through the microenvironment in which it resides.
Moreover, they have defined key elements of the stem cell niche in the bone marrow and how these features may be modified to improve stem cell number and function. They are now applying these to in vitro models adaptable to high throughput chemical and genetic analyses to further understand niche-stem cell interactions and how they might be modified therapeutically.
Research and Publications
Adams GB, Alley I, Chung, U, Chabner K, Jeanson N, Lo Celso C, Marsters E, Chen M, Weinstein L, Lin CP, Kronenberg H, Scadden DT. Bone marrow homing of hematopoietic stem cells is dependent upon G Lo Celso C, Fleming HE, Wu JW, Zhao CX, Miake-Lye S, Fujisaki J, Cote D, Rowe DW, Lin CP, Scadden DT. Live-animal tracking of individual hematopoietic stem cells in their niche. Nature 2009 Jan 1;457(7225):92-6. Epub 2008 Dec 3. Orford, K., Kharchenko, P., Lai, W., Dao, M.C., Worhunsky, D.J., Ferro, A., Janzen, V., Park, P.J., and Scadden, DT. Differential H3K4 methylation identifies developmentally poised hematopoietic genes. Developmental Cell MT, Lo Celso C, Reynolds G, Milne CD, Paige CJ, Karlsson S, Woo M, Scadden DT. Stem cell responses to exogenous signals limited by Caspase-3. Cell Stem Cell. 2008 Jun 5;2(6):584-94. Mukherjee S, Raje N, Schoonmaker J., Liu JC, Hideshima T, Wein MN, Jones DC, Vallet S, Bouxsein M, Pozzi S, Chhetri S, Seo YD, Aronson JP, Fulciniti M, Purton L , Glimcher L, Lian J, Stein, G , Glimcher L, Anderson KC, Scadden DT. Therapeutic targeting of a stem cell population Lu J, Guo S, Ebert BL, Zhang H, Peng X, Bosco J, Pretz J, Schlanger R, Wang JH, Mak RH, Dombkowski DM, Preffer FII, Scadden DT, Golub TR. microRNA-mediated control of cell fate in megakaryocyte-erythrocyte progenitors. Developmental Cell 2008 May;14(5):798-809. Fleming HE, Janzen, V, Lo Celsol C, Guo J, Leahy KM, Kronenberg HM, Scadden DT. Wnt Signaling in the Niche Enforces Hematopoietic Stem Cell Quiescence and Is Necessary to Preserve Self-Renewal in Vivo. Cell Stem Cell 2, 274-283, 2008 March. Larsson J, Ohishi M, Garrison B, Aspling M, Janzen V, Adams GB, Curto M, McClatchey AI, Schimpani E, Scadden DT. NF2/merlin regulates hematopoietic stem cell behavior by altering microenvironmental architecture. Cell Stem Cell. 2008 7;3(2):221-7. Spitzer TR, Ambinder RF, Lee JY, Kaplan LD, Wachsman W, Straus DJ, Aboulafia DM, Scadden DT. Dose-reduced busulfan, cyclophosphamide, and autologous stem cell transplantation for human immunodeficiency virus-associated lymphoma: AIDS Malignancy Consortium Study 020. Biol Blood Marrow Transplant. 2008 Jan;14(1):59-66. Kim WJ, Okimoto RA, Purton LE, Goodwin M, Haserlat SM, Dayyani F, Sweester DA, McClatchey AI, Bernard Oal, Look AT, Bell DW, Scadden DT, Haber DA. Mutations in the neutral sphingomyelinase gene SMPD3 implicate the ceramide pathway in human leukemias. Blood. 2008 Feb 25; [Epub ahead of print]. Orford K, Scadden DT. Deconstructing stem cell self-renewal: Genetic insights into cell cycle regulation. Nature Reviews Genetics. 2008 Feb; 9(2); 115-28.