Increased reactive oxygen species and exhaustion of quiescent CD34-positive bone marrow cells may contribute to poor graft function after allotransplants

• Published in: Oncotarget Vol. 7; no. 21; pp. 30892 - 30906
• Main Authors: Kong, Yuan, Song, Yang, Hu, Yue, Shi, Min-Min, Wang, Yu-Tong, Wang, Yu, Zhang, Xiao-Hui, Xu, Lan-Ping, Liu, Kai-Yan, Deng, Hong-Kui, Huang, Xiao-Jun
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 24.05.2016
• Subjects: Acetylcysteine - pharmacology; Adult; Allografts - pathology; Animals; Antigens, CD34 - metabolism; Apoptosis; Bone Marrow - metabolism; Bone Marrow - pathology; Caspase 3 - metabolism; Caspase 9 - metabolism; Colony-Forming Units Assay; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; DNA Breaks, Double-Stranded; Female; Graft vs Host Disease - complications; Hematologic Neoplasms - therapy; Hematopoietic Stem Cell Transplantation - adverse effects; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Humans; Hydrogen Peroxide - adverse effects; Male; Mice; Mice, Inbred NOD; Middle Aged; Prospective Studies; Reactive Oxygen Species - adverse effects; Research Paper; Resting Phase, Cell Cycle; Transplantation, Heterologous - adverse effects; Transplantation, Homologous - adverse effects; Tumor Suppressor Protein p53 - metabolism; Up-Regulation; Young Adult; allotransplant; haematopoietic stem cells; reactive oxygen species; poor graft function
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.8810

Poor graft function (PGF) is a fatal complication following allogeneic haematopoietic stem cell transplantation. However, the underlying mechanism is unclear. Effective cross-talk between haematopoietic stem cells (HSCs) and bone marrow microenvironment is important for normal haematopoiesis. Normal HSCs reside in a hypoxic bone marrow microenvironment that protects them from oxidative stress that would otherwise inhibit their self-renewal and results in bone marrow failure. Whether an increased level of reactive oxygen species (ROS) causes PGF following allotransplant is unclear. Using a prospective case-pair study, we identified increased levels of ROS in CD34+ bone marrow cells in subjects with PGF. Elevated ROS levels was associated with an increased frequency of DNA strand breaks, apoptosis, exhaustion of quiescent CD34+ cells and defective colony-forming unit plating efficiency, particularly in the CD34+CD38- fraction. Up-regulated intracellular p53, p21, caspase-3 and caspase-9 levels (but not p38) were detected in CD34+ cells, particularly in the CD34+CD38- fraction. To further study the potential role of ROS levels in post-transplant haematopoiesis, CD34+ bone marrow cells from subjects with good graft function were treated with H2O2. This increased ROS levels resulting in defective CD34+ cells, an effect partially reversed by N-acetyl-L-cysteine. Moreover, CD34+ bone marrow cells from the donors to subjects with poor or good graft function exhibited comparable haematopoietic reconstitution capacities in the xeno-transplanted NOD-PrkdcscidIL2rgnull mice. Thus, even if the transplanted donors' bone marrow CD34+ cells are functionally normal pre-transplant, ROS-induced apoptosis may contribute to the exhaustion of CD34+ bone marrow cells in subjects with PGF following allotransplant.