AKT1 and AKT2 maintain hematopoietic stem cell function by regulating reactive oxygen species

• Published in: Blood Vol. 115; no. 20; pp. 4030 - 4038
• Main Authors: Juntilla, Marisa M., Patil, Vineet D., Calamito, Marco, Joshi, Rohan P., Birnbaum, Morris J., Koretzky, Gary A.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 20.05.2010; Americain Society of Hematology; American Society of Hematology
• Series: Hematopoiesis and Stem Cells
• Subjects: Animals; Antigens, CD - metabolism; Biological and medical sciences; CD48 Antigen; Cell Differentiation; Cell Lineage; Flow Cytometry; Hematologic and hematopoietic diseases; Hematopoiesis - physiology; Hematopoiesis and Stem Cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - physiology; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Proto-Oncogene Proteins c-akt - physiology; Reactive Oxygen Species - metabolism; Receptors, Cell Surface - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signaling Lymphocytic Activation Molecule Family Member 1; Hematopoietic cell; Oxidative stress; Reactive oxygen species; Cell function; Hematology; Stem cell
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-09-241000

Although AKT is essential for multiple cellular functions, the role of this kinase family in hematopoietic stem cells (HSCs) is unknown. Thus, we analyzed HSC function in mice deficient in the 2 isoforms most highly expressed in the hematopoietic compartment, AKT1 and AKT2. Although loss of either isoform had only a minimal effect on HSC function, AKT1/2 double-deficient HSCs competed poorly against wild-type cells in the development of myeloid and lymphoid cells in in vivo reconstitution assays. Serial transplantations revealed an essential role for AKT1 and AKT2 in the maintenance of long-term HSCs (LT-HSCs). AKT1/2 double-deficient LT-HSCs were found to persist in the G0 phase of the cell cycle, suggesting that the long-term functional defects are caused by increased quiescence. Furthermore, we found that the intracellular content of reactive oxygen species (ROS) is dependent on AKT because double-deficient HSCs demonstrate decreased ROS. The importance of maintaining ROS for HSC differentiation was shown by a rescue of the differentiation defect after pharmacologically increasing ROS levels in double-deficient HSCs. These data implicate AKT1 and AKT2 as critical regulators of LT-HSC function and suggest that defective ROS homeostasis may contribute to failed hematopoiesis.