Increased reactive oxygen species and exhaustion of quiescent CD34-positive bone marrow cells may contribute to poor graft function after allotransplants
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Yuan Kong1,*, Yang Song1,2,*, Yue Hu1,2, Min-Min Shi1,2, Yu-Tong Wang1, Yu Wang1, Xiao-Hui Zhang1, Lan-Ping Xu1, Kai-Yan Liu1, Hong-Kui Deng2,3, Xiao-Jun Huang1,2
1Peking University People’s Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
2Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
3Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China
*These authors have contributed equally to this work
Xiao-Jun Huang, email: [email protected]
Keywords: poor graft function, allotransplant, haematopoietic stem cells, reactive oxygen species
Received: February 02, 2016 Accepted: March 31, 2016 Published: April 18, 2016
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.
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