Stefan Karlsson Professor of Molecular Medicine Head, Molecular Medicine and Gene Therapy
Address:	Lund University Hospital BMC A12 221 84 Lund Sweden Phone +46 46 2222 05 77 Fax +46 46 222 05 78 E-mail Stefan.Karlsson@molmed.lu.se

Main Research Topics Laboratory Members Selected Recent and Key Publications Link to Molecular Medicine Home Page

Main Research Topics Hematopoiesis and Gene Therapy of Hematopoietic Stem Cells The main focus of our research is to develop gene therapy for hematopoietic cells, particularly hematopoietic stem cells. Similarly, there is a strong effort to study the genetic regulation of hematopoietic stem cell proliferation in novel animal models created in the department. Hematopoietic stem cells are interesting target cells for gene therapy because they have an enormous proliferative capacity and can be used to repopulate the entire hematopoietic system in humans and experimental animals following bone marrow transplantation. Following effective gene transfer into hematopoietic stem cell of a patient, the genetically modified cells can be transplanted back to the patient and will be expected to produce genetically corrected cells of all blood lineages for a long time, perhaps for a lifetime. To achieve our goals we are developing viral vectors to transfer genes into hematopoietic stem cells. Similarly, we study the target cells for the viral vectors, the hematopoietic stem cells. Of major importance for effective gene transfer of hematopoietic stem cells is their cell cycle stage. Quiescent, nondividing stem cells are difficult targets for gene transfer, but more activated cells and cells that are dividing are generally more susceptible to gene transfer. Therefore, we study the proliferation of hematopoietic stem cells in mutant mice that we have created in the department. These models have forced expression (gain-of-function) or gene deletion (lack-of-function) to modulate cell proliferation within the hematopoietic system. Mice that can be induced to eliminate or block the function of the TGF-b negative growth regulatory pathway have been generated and are used to study how this affects the function, proliferation and development of hematopoietic stem cells. Similar questions are studied in mice that can be induced to overexpress or lack Hox transcription factors which normally stimulate proliferation of hematopoietic stem cells. Taken together, we focus on the development of gene therapy for hematopoietic stem cells, while simultaneously studying thedevelopment and proliferation of these target cells for gene therapy in novel engineered animal models. Laboratory Members Björnsson, Jon Mar, PhD student Blank, Ulrika, PhD student Brun, Ann, MSc, PhD student Fan, Xiaolong, PhD, research assoc Flygare, Johan, PhD student Ingloff, Margareta, secretary Johansson, Maria, graduate student Karlsson, Göran, graduate student Karlsson, Stefan, MD, PhD, professor Kiefer, Thomas, MD, research fellow Larsson, Jonas, MD, PhD student Levéen, Per, PhD, research assoc Magnusson, Mattias, PhD student Nilsson, Eva, research engineer Nilsson, Marcus, graduate student Olsson, Karin, laboratory technician Ooka, Andreas, PhD student Relander, Thomas, MD, PhD student Richter, Johan, MD, PhD, physician Woods, Niels-Bjarne, PhD student + 46 (0) 46 2220589 + 46 (0) 46 2220593 + 46 (0) 46 2220592 + 46 (0) 46 2220580 + 46 (0) 46 2220590 + 46 (0) 46 2220575 + 46 (0) 46 2220593 + 46 (0) 46 2220593 + 46 (0) 46 2220577 + 46 (0) 46 2220592 + 46 (0) 46 2220589 + 46 (0) 46 2220589 + 46 (0) 46 2220589 + 46 (0) 46 2220592 + 46 (0) 46 2220590 + 46 (0) 46 2220590 + 46 (0) 46 2220590 + 46 (0) 46 2220592 + 46 (0) 46 2220587 + 46 (0) 46 2220590 Selected Recent and Key Publications Kulkarni, A.B., Huh, C., Becker, D., Lyght, M., Geiser, A., Roberts, A.B., Sporn, M.B., Ward, J.M., Karlsson, S. (1993). Transforming growth factor-beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl. Acad. Sci. USA 90: 770-774. Migita, M., Medin, J.A., Pawliuk, R., Jacobson, S., Amiri, M., Humphries, R.K., Karlsson, S. (1995). Selection of transduced CD34+ progenitors and enzymatic correction of cells from Gaucher patients, using bicistronic vectors. Proc Natl Acad Sci USA 92: 12075-12079. Karlsson, S. (2000). The first steps on the gene therapy pathway to anti-sickling success. Nature Medicine 6: 139-140. Woods, N-B, Fahlman, C, Mikkola, H, Hamaguchi, I, Olsson, K, Zuffereey R, Jacobsen, SEW, Trono, D, Karlsson, S (2000). Lentiviral gene transfer into primary and secondary NOD/SCID repopulating cells. Blood 96:3725-3733. Larsson, J, Goumans M-J, Jansson-Sjöstrand L, van Rooijen M, Ward, D, Levéen, P, Xu, X, ten Dijke, P, Mummery, C L, Karlsson, S (2001). Abnormal vascular development, but intact hematopoietic potential in transforming growth factor-ß receptor I deficient mice. EMBO J 20: 1663-1673. Björnsson, JM, Andersson, E, Lundström, P, Larsson, N, Repetowska, E, Humphries, RK, Karlsson, S (2001). Proliferation of primitive myeloid progenitors can be reversibly induced by HoxA10. Blood 98: 3301-3308. Fan, X, Valdimarsdottir, G, Larsson J, Brun, A, Magnusson, M, Jacobsen SE, ten Dijke, P, Karlsson, S (2002). Transient disruption of autocrine transforming growth factor-b signalling leads to enhanced survival and proliferation potential in single primitive human hematopoietic progenitor cells. J Immunol 168: 755-762. Levéen, P, Larsson, J, Ehinger, M, Mikkola, H, Jansson, L, Xu, X, Karlsson, S (2002). Induced disruption of the transforming growth factor-ß type II receptor gene in mice leads to a lethal inflammatory disease that is transplantable. Blood 100:560-568. Hamaguchi, I, Ooka, A, Richter, J, Dahl, N, Karlsson, S (2002). Gene transfer improves erythroid development in ribosomal protein S19 deficient Diamond-Blackfan Anemia. Blood 100: 2724-2731. Woods, N-B, Muessig, A, Schmidt M, Flygare, J, Olsson, K, Salmon, P, Trono, D, von Kalle, C, Karlsson, S (2003). Lentiviral vector transduction of NOD/SCID repopulating cells results in multiple vector integrations per transduced cell: risk of insertional mutagenesis.Blood 101:1284-9 Hamaguchi, I, Nishiura, H, Flygare, J, Brun, A, Dahl, N, Richter, J, Karlsson, S. (2003). Multipotent hematopoietic progenitors from ribosomal protein S19 (RPS19) deficient Diamond-Blackfan anemia patients exhibit a proliferation deficiency which improves upon enforced expression of RPS19. Molecular Therapy 7: 613-622. Björnsson JM, Larsson N, Brun, A, Magnusson, M Andersson, E, Lundström, P, , Larsson J, Repetowska E, Ehinger, M, Humphries, RK, Karlsson S (2003). Reduced proliferative capacity of hematopoietic stem cells deficient in Hoxb3 and HoxB4. Mol. Cellular Biol. 23: 3872-3883.