Protein kinase B (PKB/c-akt) regulates homing of hematopoietic progenitors through modulation of their adhesive and migratory properties.
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 β2-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.
Buitenhuis
Miranda
M
Molecular Immunology Laboratory, Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands. m.buitenhuis@erasmusmc.nl
van der Linden
Edwin
E
Ulfman
Laurien H
LH
Hofhuis
Frans M
FM
Bierings
Marc B
MB
Coffer
Paul J
PJ
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D003114:Colony-Forming Units Assay; D036101:Cord Blood Stem Cell Transplantation; D005312:Fetal Blood / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D007231:Infant, Newborn; D016023:Integrins / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000235:genetics
D018952:Antigens, CD34; D016023:Integrins; D047428:Protein Kinase Inhibitors; D001613:beta 2-Microglobulin; D051057:Proto-Oncogene Proteins c-akt