Exp Hematol. 2016 Sep 16. pii: S0301-472X(16)30613-0. doi: 10.1016/j.exphem.2016.09.003. [Epub ahead of print]

Pharmacological inhibition of AKT activity in human CD34+ cells enhances their ability to engraft immunodeficient mice.

Chen S¹, Gao R², Kobayashi M², Yu H², Yao C³, Kapur R², Yoder MC², Liu Y⁴.

Abstract

Although practiced clinically for more than 40 years, the use of hematopoietic stem cell (HSC) transplants remains limited by the ability to expand functional HSCs ex vivo. To determine the role of PI3K/AKT signaling in human hematopoietic stem and progenitor cell (HSPC) maintenance, we examined the effect of genetic and pharmacological inhibition of AKT on human cord blood CD34⁺ cells. We found that knockdown of AKT1 in human cord blood CD34⁺ cells using siRNAs targeting AKT1 enhances their quiescence and colony formation potential in vitro. We treated human cord blood CD34⁺ cells with an AKT-specific inhibitor (AKTi) and performed both in vitro and in vivo stem and progenitor cell assays. We found that ex vivo treatment of human HSPCs maintains CD34 expression and enhances colony formation in serial replating assays. Moreover, pharmacological inhibition of AKT enhances the short-term repopulating potential of human cord blood CD34⁺ cells in immunodeficient mice. Mechanistically, genetic and pharmacological inhibition of AKT activity promotes human HSPC quiescence. These pre-clinical results suggest a positive role for AKT inhibitor during ex vivo culture of human cord blood HSPCs.