aSupported in part by National Heart, Lung, and Blood Institute Program Project Grant No. P01 HL 53749, The James S. McDonnell Foundation Grant No. 94-50, US Public Health Service Grant No. P01 CA 31922, Cancer Center Support Grant No. P30 CA 21765, and the American Lebanese Syrian Associated Charities (ALSAC).
Effects of Retroviral-Mediated MDR1 Expression on Hematopoietic Stem Cell Self-Renewal and Differentiation in Culturea
Article first published online: 6 FEB 2006
Annals of the New York Academy of Sciences
Volume 872, HEMATOPOIETIC STEM CELLS BIOLOGY AND TRANSPLANTATION pages 125–141, April 1999
How to Cite
BUNTING, K. D., GALIPEAU, J., TOPHAM, D., BENAIM, E. and SORRENTINO, B. P. (1999), Effects of Retroviral-Mediated MDR1 Expression on Hematopoietic Stem Cell Self-Renewal and Differentiation in Culture. Annals of the New York Academy of Sciences, 872: 125–141. doi: 10.1111/j.1749-6632.1999.tb08459.x
- Issue published online: 6 FEB 2006
- Article first published online: 6 FEB 2006
Abstract: Ex vivo expansion of hematopoietic stem cells would be useful for bone marrow transplantation and gene therapy applications. Toward this goal, we have investigated whether retrovirally-transduced murine stem cells could be expanded in culture with hematopoietic cytokines. Bone marrow cells were transduced with retroviral vectors expressing either the human multidrug resistance 1 gene (HaMDR1), a variant of human dihydrofolate reductase (HaDHFR), or both MDR1 and DHFR in an internal ribosomal entry site (IRES)-containing bicistronic vector (HaMID). Cells were then expanded for 15 days in cultures stimulated with interleukin (IL)-3, IL-6, and stem cell factor. When very low marrow volumes were injected into lethally irradiated recipient mice, long-term reconstitution with 100% donor cells was seen in all mice injected with HaMDR1- or HaMID-transduced cells. By contrast, engraftment with HaDHFR- or mock-transduced cells ranged from partial to undetectable despite injection of significantly larger marrow volumes. In addition, mice transplanted with expanded HaMDR1- or HaMID-transduced stem cells developed a myeloproliferative disorder that was characterized by an increase in abnormal peripheral blood leukocytes. These results show that MDR1-transduced stem cells can be expanded in vitro with hematopoietic cytokines, but indicate that an increased stem cell division frequency can lead to stem cell damage.