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Stem Cells, Vol. 18, No. 5, 352-359, September 2000
© 2000 AlphaMed Press

Lentiviral Vector Transduction of Hematopoietic Stem Cells that Mediate Long-Term Reconstitution of Lethally Irradiated Mice

WenYong Chena,e, Xiaoyun Wub, Dana N. Levasseura, Hongmei Liub, Lilin Laib, John C. Kappesb,c,d, Tim M. Townesa

a Department of Biochemistry and Molecular Genetics,
b Department of Medicine,
c Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA;
d Birmingham Veterans Affairs Medical Center Research Service, Birmingham, Alabama, USA;
e Current address: Johns Hopkins Oncology Center-Tumor Biology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Key Words. Lentiviral vector • VSV-G • Sca-1+ c-Kit+Lin • cells • Transplantation

Tim M. Townes, M.D., Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, BBRB 870, 845 19th Street South, Birmingham, Alabama 35294, USA. Telephone: 205-934-5294; Fax: 205-934-2889; e-mail: ttownes{at}uab.edu

Lentiviral vectors efficiently transduce human CD34+ cells that mediate long-term engraftment of nonobese diabetic/severe combined immunodeficient mice. However, hematopoiesis in these animals is abnormal. Typically, 95% of the human cells in peripheral blood are B lymphocytes. To determine whether lentiviral vectors efficiently transduce stem cells that maintain normal hematopoiesis in vivo, we isolated Sca-1+c-Kit+Lin– bone marrow cells from mice without 5-fluorouracil treatment, and transduced these cells in the absence of cytokine stimulation with a novel lentiviral vector containing a GFP (green flourescent protein) reporter gene. These cells were transplanted into lethally irradiated C57Bl/6 mice. In fully reconstituted animals, GFP expression was observed in 8.0% of peripheral blood mononuclear cells for 20 weeks posttransplantation. Lineage analysis demonstrated that a similar percentage (approximately 8.0%) of GFP-positive cells was detected in peripheral blood B cells, T cells, granulocytes and monocytes, bone marrow erythroid precursor cells, splenic B cells, and thymic T cells. In secondary transplant recipients, up to 20% of some lineages expressed GFP. Our results suggest that quiescent, hematopoietic stem cells are efficiently transduced by lentiviral vectors without impairing self-renewal and normal lineage specification in vivo. Efficient gene delivery into murine stem cells with lentiviral vectors will allow direct tests of genetic therapies in mouse models of hematopoietic diseases such as sickle cell anemia and thalassemia, in which corrected cells may have a selective survival advantage.




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