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David T. Scadden, M.D.Gerald and Darlene Jordan Professor of Medicine, Harvard UniversityDirector, Center for Regenerative Medicine, Massachusetts General HospitalCo-Director, Harvard Stem Cell Institute, Harvard UniversityCo-Chair, Department of Stem Cell and Regenerative Biology, Harvard UniversityChief, Hematologic Malignancies, MGH Cancer Centerdscadden@mgh.harvard.edu
Dr. Scadden's laboratory is focused on hematopoietic stem cell biology. We 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. We 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, our group uses both comparative genomics and shRNA forward screening to identify candidate mediators of the self-renewal program in hematopoietic stem cells. Second, we are studying stem cell localization as delivery of stem cells to specific sites is critical for their application clinically. We 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, we are deeply interested in viewing the stem cell through the microenvironment in which it resides. We 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. We 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.
Assistant ProfessorsJorg Dietrich, M.D., Ph.D.David Sykes, M.D., Ph.D.
InstructorsYing-Hua Wang, PhDVionnie Yu, Ph.D.Rushdia Yusuf, M.DResearch FellowsNinib Baryawno, Ph.D.Karin Gustafsson, Ph.D.Jonathan Hoggatt, Ph.D.Demetrios Kalaitzidis, Ph.D.Youmna Kfoury, Ph.D.Dongjun Lee, Ph.D. Hong Mei, M.D. Francois Mercier, M.D. Toshihiko Oki, M.D.,Ph.D.Rahul Palchaudhuri, Ph.D. Dongsu Park, Ph.D. Borja Saez, Ph.D. Amir Schajnovitz, Ph.D. Nicolas Severe, Ph.D. Lev Silberstein, M.D., Ph.D.
Research TechniciansJacqueline BachandCam Dung LiKatrina MaxcyTiffany Tate
StudentBess MillerHannah RasmussenLatoya Stewart
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 Gsa-mediated signalling. Nature. 2009 Mar 25. [Epub ahead of print]
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. 2008 May; 14(5): 798-809.
Janzen V, Fleming H, Riedt T, Karlsson G, Riese 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 in vivo is associated with enhanced bone regeneration. J Clin Invest. 2008 Feb 1;118(2):491-504.
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
Scadden D. Circadian rhythms: stem cells traffic in time. Nature. 2008 March 27;452(7186);416-7
Papayannopoulou T, Scadden DT. Stem-cell ecology and stem cells in motion. Blood. 2008 Apr 15;111(8):3923-30.
Craiu A, Scadden D. Flow electroporation with pulsed electric fields for purging tumor cells. Methods Mol Biol. 2008;423:301-10.
Raaijmakers MH, Scadden DT. Evolving concepts on the microenvironmental niche for hematopoietic stem cells. Curr Opin Hematol. 2008 Jul;15(4):301-6. Review.
Purton LE, Scadden DT. Limiting factors in murine hematopoietic stem cell assays. Cell Stem Cell. 2007 Sep 13;1(3):263-70. Review.
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