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Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 902-909
Enforced P-glycoprotein pump function in murine bone marrow cells
results in expansion of side population stem cells in vitro and
repopulating cells in vivo
Kevin D. Bunting,
Sheng Zhou,
Taihe Lu, and
Brian P. Sorrentino
From the Division of Experimental Hematology, Department of
Hematology/Oncology, and the Department of Biochemistry, St. Jude
Children's Research Hospital, Memphis, TN.
The human multidrug resistance-1 (MDR1) gene product,
P-glycoprotein (P-gp), is well known for its ability to confer drug resistance; however, recent evidence suggests that P-gp expression can
have more general effects on cellular development. In support of this
idea, it was previously shown that retroviral-mediated MDR1 expression
in murine bone marrow cells resulted in the expansion of stem cells in
culture and in the development of a myeloproliferative syndrome in
transplanted mice. It is now reported that MDR1-mediated stem cell
expansion is associated with an increase in side population (SP) stem
cells, defined by Hoechst dye staining. Transduction of murine bone
marrow cells with an MDR1 retroviral vector resulted in an almost 2 log
increase in SP cell numbers over 12 days in culture, whereas there was
a rapid loss of SP cells from control cultures. Stem cell amplification
was not limited to ex vivo expansion cultures but was also evident when
MDR1-transduced cells were directly transplanted into irradiated mice.
In these cases, stem cell expansion was associated with relatively high
vector copy numbers in stem cell clones. As previously reported, some
cases were associated with a characteristic myeloproliferative
syndrome. A functionally inactive MDR1 mutant cDNA was used to show
that P-gp pump function was required both for amplification of
phenotypically defined SP cells and functionally defined repopulating
cells. These studies further support the concept that ABC transporter function can have important effects on hematopoietic stem cell development.
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