George Murphy, PhD
|PI: George Murphy, PhD
Title: Assistant Professor of Medicine
Research Interests: Hematopoiesis, megakaryocyte development, stem cell biology, and gene and cell-based therapies.
The Murphy Lab is a basic science and translational laboratory in the Section of Hematology and Oncology in the Department of Medicine at Boston University and the Boston Medical Center. Our goal is to advance the understanding of hematopoiesis, megakaryocytopoiesis, and stem cell biology, using the knowledge gained to forge applications for disorders of the blood. As developments borne in basic research are translated directly into therapies applied in the clinic, the long term objectives of our work are to develop stem and cell-based therapies aimed at combating blood-borne diseases such as sickle cell anemia, amyloidosis, and various thrombotic disorders.
Specific Areas of Research:
The connection between stem cells and megakaryocytes
In the heirarchical ordering of the hematopoietic system, the pluripotent stem cell is the starting point, for it is the cell from which all others arise, including the megakaryocyte. Found at one of the end points of the system, the fully differentiated megakaryocyte takes its place as one the eight distinct blood cell types found within the bone marrow. Although the pluripotent stem cell and the megakaryocyte are found at opposite ends of the hematopoietic spectrum, these cell types are linked in ways other than the fact that the stem cell gives rise to the megakaryocyte. Both the hematopoietic stem cell and the megakaryocyte are rare cells within the bone marrow, with stem cells remaining quiescent for long periods of time, and megakaryocytes representing less than < 0.5% of the entire bone marrow population. This rarity, along with a paucity of useful reagents in which to study these cell types, link both populations by making them incredibly difficult to access by researchers working in the field of hematopoiesis. In addition, both hematopoietic stem cells (HSC) and megakaryocytes are linked by the fact that they both have very special properties and make complex fate choices to proliferate or to differentiate. HSC can either self renew or produce all the defined lineages of the hematopoietic system, and megakaryocytes can differentiate into low or high ploidy cells with only the high ploidy cells, which no longer divide but continue to increase their nuclear content (endoreplication), able to go on to produce platelets. Lastly, the cell populations are also linked by recent studies in our laboratory and others which have shown that expression profiles comparing HSC vs. Non-HSC populations reveal the robust, differential expression of several megakaryocyte-specific genes.
Hematopoietic cell gene transfer
Recent conceptual and technical improvements have resulted in clinically meaningful levels of gene transfer into repopulating hematopoietic stem cells. We currently employ novel, highly efficient gene transfer strategies and methodologies in our laboratory which have lead to new ways of studying and manipulating HSC, opening the door to possible human gene therapy approaches. In addition, we are currently employing new technologies and methodologies aimed at obtaining megakaryocyte-specific infection and regulated expression.
iPS cells and hematopoiesis
The reprogramming of somatic cells into induced pluripotent stem (iPS) cells (Takahashi and Yamanaka, 2006) is a breakthrough discovery with the potential to be developed into a wide array of clinical applications. A variety of human somatic cells have been effectively reprogrammed, albeit at limited efficiencies, and their murine counterparts have been shown to have efficacy in the treatment of disease models. A major goal of our laboratory is the direct application of this technology to the study of the hematopoietic system and blood borne diseases. The iPS technology currently being developed in our lab will allow for the creation of advanced disease models of the blood and may allow for the production of “custom” hematopoietic stem cells and fully differentiated hematopoietic cells for cell-based therapies that match the patient’s immunologic profile.
Murphy, G.J. and Leavitt A.D. (1999) A model for studying megakaryocyte development and biology. Proc. Natl. Acad. Sci. USA,96,3065-3070.
Shiraga, M., Ritchie A., Aidoudi, S., Baron V., Wilcox, D., White G., Ybarrondo, B., Murphy, G., Leavitt, A., Shattil, S. (1999) Primary megakaryocytes reveal a role for transcription factor NF-E2 in integrin alpha IIb beta3 signaling. J Cell Biol,147,1419-1430.
Berlanga O, Bobe R, Murphy G, Leduc M, Bon C, Barry FA, Gibbins JM, Garcia P, Frampton J, Watson SP. (2000) Expression of the collagen receptor glycoprotein VI during megakaryocyte differentiation. Blood, 96(8),2740-2745.
Gaur M, Murphy GJ, deSauvage FJ, and Leavitt AD. (2001) Characterization of Mpl mutants using primary megakaryocyte-lineage cells from mpl-/- mice: a new system for Mpl structure-function studies. Blood, 97(6), 1653-1661.
Emambokus NR, Murphy GJ, and Frampton J. (2002) Manipulation of gene expression in megakaryocytes, in Platelets and Megakaryocytes: Methods and Protocols, Editors J.M. Gibbins and M.P. Mahaut-Smith.
Gaur M, Murphy GJ, Frampton J, and Leavitt AD. (2002) Using retroviruses to express genes in primary megakaryocyte lineage cells, in Platelets and Megakaryocytes: Methods and Protocols, Editors J.M. Gibbins and M.P. Mahaut-Smith.
Murphy GJ, Göttgens B, Vegiopoulos Sanchez MJ, Leavitt AD, Watson SP, Green AR, and Frampton J. (2003) Manipulation of mouse hematopoietic progenitors by specific retroviral infection. Journal of Biological Chemistry, 44, 43556-43563.
Gottgens B, Broccardo C, Sanchez MJ, Deveaux S, Murphy G, Gothert JR, Kotsopoulou E, Kinston S, Delaney L, Piltz S, Barton LM, Knezevic K, Erber WN, Begley CG, Frampton J, Green AR. (2004) The scl+18/19 stem cell enhancer is not required for hematopoiesis: identification of a 5′ bifunctional hematopoietic-endothelial enhancer bound by Fli-1 and Elf-1. Mol Cell Biol., 24, 1870-1883.
Murphy GJ, Mostoslavsky G, Kotton DN, Mulligan RC. (2006) Exogenous control of mammalian gene expression via modulation of translational termination. Nature Medicine, 9, 1093-1099.
Sommer CA, Stadtfeld M, Murphy GJ, Hochedlinger K, Kotton DN, and Mostoslavsky G. (2008) iPS generation using a single lentiviral stem-cell cassette. Stem Cells, December 18 (epub ahead of print).