Cyclosporine May Inhibit the Effect of Extra-Physiologic Oxygen Shock/Stress on Peripheral Blood Stem Cells

Introduction: Adequate numbers of stem cells with preserved multi-potency and self-renewing capabilities are necessary for successful hematopoietic reconstitution after bone marrow transplantation. Although hematopoietic stem cells (HSC) reside in the bone marrow under a hypoxic microenvironment (1-4% O2), human HSC are collected and processed in ambient air (21% O2) (Spencer et al., Nature 508:269-73). Exposure of murine bone marrow and human cord blood to ambient air for as little as 30 minutes triggered stem cell differentiation from quiescent pluripotent long term stem cells into activated multipotent progenitors (MPPs), a phenomenon called extra-physiologic oxygen shock / stress (EPHOSS)(Mantel et al., Cell 161:1553-65). The effect of EPHOSS on HSCs is mediated through reactive oxygen species (ROS) which open the mitochondrial permeability transition pore (MPTP) and trigger stem cell differentiation. Cyclosporine (CSA) inhibits the MPTP regulator cyclophilin D and prevents MPTP opening (Kroemer et al., Physiol Rev 87:99-163). Currently, mobilized peripheral blood stem cells (PBSCs) are the major source of grafts for hematopoietic cell transplantation. We hypothesized that EPHOSS is detrimental to human PBSCs similar to murine bone marrow and human cord blood stem cells and CSA will protect human PBSCs from the effects of EPHOSS and inhibit their differentiation from pluripotent long term HSC into short term MPPs.