Molecular Immunology Laboratory, Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Blood. 2010 Sep 30;116(13):2373-84. doi: 10.1182/blood-2009-10-250258. Epub 2010 Jun 21.
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.
脐带血（UCB）中的造血干细胞数量有限，这在使用 UCB 进行干细胞移植时是一个问题。提高其归巢能力可以减少移植过程中对高初始细胞数量的需求。尽管很明显蛋白激酶 B（PKB/c-Akt）在调节各种细胞类型的迁移中起着重要作用，但 PKB 在调节人类造血干细胞和祖细胞的迁移和归巢中的作用仍有待确定。发现 PKB 活性对于诱导与骨髓来源的基质细胞的黏附是必需的，并且对 UCB 来源的 CD34(+)造血祖细胞的迁移是有害的。此外，发现 PKB 活性正向调节整合素的表达。CD34(+)造血祖细胞及其在体外形成集落的能力不受 PKB 的瞬时抑制影响。最后，将异位表达组成性激活 PKB 的 CD34(+)细胞移植到β2-微球蛋白(-/-)非肥胖型糖尿病/严重联合免疫缺陷小鼠中，导致向骨髓的迁移减少，而抑制 PKB 活性则导致骨髓归巢和植入的诱导。这些结果表明，PKB 活性的短暂抑制可能为体外干细胞操作提供一种手段，以改善骨髓移植方案。
