Protein kinase B (PKB/c-akt) regulates homing of hematopoietic progenitors through modulation of their adhesive and migratory properties

被引:15
作者
Buitenhuis, Miranda [1 ]
van der Linden, Edwin [1 ]
Ulfman, Laurien H. [2 ]
Hofhuis, Frans M.
Bierings, Marc B. [3 ]
Coffer, Paul J. [1 ,4 ]
机构
[1] Univ Med Ctr Utrecht, Mol Immunol Lab, Dept Immunol, Utrecht, Netherlands
[2] Univ Med Ctr Utrecht, Dept Resp Med, Utrecht, Netherlands
[3] Univ Med Ctr Utrecht, Dept Pediat, Utrecht, Netherlands
[4] Univ Med Ctr Utrecht, Dept Pediat Immunol, Utrecht, Netherlands
关键词
UMBILICAL-CORD BLOOD; CELL-CYCLE ACTIVATION; BONE-MARROW; ENDOTHELIAL SELECTINS; STEM/PROGENITOR CELLS; ESSENTIAL MOLECULES; UNRELATED DONORS; LINEAGE CHOICE; STEM; ENGRAFTMENT;
D O I
10.1182/blood-2009-10-250258
中图分类号
R5 [内科学];
学科分类号
100201 [内科学];
摘要
Limited number of hematopoietic stem cells in umbilical cord blood (UCB) presents a problem when using UCB for stem cell transplantation. Improving their homing capacity could reduce the need for high initial cell numbers during transplantation procedures. Although it is evident that protein kinase B (PKB/c-Akt) plays an important role in regulation of migration of various cell types, a role for PKB in regulation of migration and homing of human hematopoietic stem and progenitor cells remains to be determined. PKB activity was found to be required for induction of adhesion to bone marrow-derived stromal cells and detrimental for migration of UCB-derived CD34(+) hematopoietic progenitors. In addition, PKB activity was found to positively regulate integrin expression. CD34(+) hematopoietic progenitors, and their capacity to form colonies in vitro, were not affected by transient inhibition of PKB. Finally, transplantation of beta 2-microglobulin(-/-) nonobese diabetic/severe combined immunodeficient mice with CD34(+) cells ectopically expressing constitutively active PKB resulted in reduced migration to the bone marrow, whereas inhibition of PKB activity resulted in an induction in bone marrow homing and engraftment. These results indicate that transient inhibition of PKB activity may provide a means for ex vivo stem cell manipulation to improve bone marrow transplantation regimes. (Blood. 2010; 116(13): 2373-2384)
引用
收藏
页码:2373 / 2384
页数:12
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