IntroductionMaintenance of the hematopoietic system requires continual replenishment of mature blood cells from a rare population of bone marrow residing hematopoietic stem cells (HSCs). The alteration of the homeostatic control of hematopoiesis is considered to be a major culprit of drastic increase in pathologic incidences, such as bone marrow failure, anemia, and myeloid leukemia during aging. 1 However, the underlying mechanisms of pathogenesis of hematologic malignancy in elderly population remain poorly understood.Mounting evidence supports the idea that the accumulation of somatic DNA damage is a main cause of aging in multicellular organisms. [2][3][4][5] Mice with mutations in various DNA repair genes exhibit accelerated aging in the hematopoietic system because of the premature exhaustion of HSCs, indicating that DNA repair is crucial for the maintenance of HSC self-renewal and hematopoietic function. 6,7 DNA damage can directly result from genotoxic treatment such as ionizing radiation (IR), or may simply occur as a consequence of genome duplication infidelity or of genotoxic effects of reactive oxygen species (ROS). ROS, such as superoxide anions and hydrogen peroxide, are byproducts of normal oxidative metabolism in eukaryotic cells and are involved in many signaling process. However, they can be harmful to cellular components, including DNA. 3,8,9 An uncontrolled elevation of intracellular ROS levels is believed to contribute to cellular aging and the senescence process. 3 In fact, an abnormal elevation of intracellular ROS levels has been implicated in the pathogenesis of various diseases, such as ataxia telangiectasia and Fanconi anemia. 3 In that sense, the maintenance of ROS levels, through highly regulated mechanisms, is essential for cellular homeostasis. 10 Being continuously exposed to oxidants produced during metabolic activity and to external oxidants or oxidant-inducers through normal cellular physiology, DNAs within cells inevitably suffer the oxidative damage. Therefore, an accelerated proliferation of hematopoietic cells, which is expected to occur after clinical HSC transplantation, might lead to DNA damage through overexposure to oxidative stress generated on each cell cycle. Indeed, a hyperproliferation caused an accumulation of oxidative stress and resulted in functional exhaustion of murine HSCs, as shown by the failure to reconstitute hematopoiesis after serial transplantations. 11 Taken together, we hypothesize that the continuous production of ROS during long-term repopulation induces an accumulation of genomic damage that leads to exhaustion of human HSCs. We have previously developed a strategy that enables to examine the multipotency of a single human HSC using a reliable surrogate system. 12,13 By determining the in vivo repopulating dynamics of individual human HSCs, we demonstrated that the repopulating potential of the majority of human HSCs progressively deteriorated as they underwent extensive repopulation process. Furthermore, the self-renewing long-term repopulating...

Background-Hematopoietic cytokines, granulocyte colony-stimulating factor (G-CSF), and stem cell factor (SCF) were reported to show a neuroprotective effect or to support neurogenesis. These cytokines also mobilize bone marrow (BM) cells into the brain, and the BM-derived cells differentiate into neuronal cells. We administered these hematopoietic cytokines after focal cerebral ischemia and assessed their effects and the therapeutic time window for neuronal regeneration. Methods and Results-We induced permanent middle cerebral artery occlusion in mice whose BM had been replaced with BM cells from green fluorescent protein (GFP)-transgenic mice. The occluded mice were treated with G-CSF and SCF in the acute phase (days 1 to 10) or subacute phase (days 11 to 20), and the brain functions and histological changes were evaluated. Separately, we injected bromodeoxyuridine during cytokine treatment to assess cell kinetics in the brain. Six mice were prepared for each experimental group. Administration of G-CSF and SCF in the subacute phase effectively improved not only motor performance but also higher brain function, compared with acute-phase treatment. Acute-phase and subacute-phase treatments identically reduced the infarct volume relative to vehicle treatment. However, subacute-phase treatment significantly induced transition of BM-derived neuronal cells into the peri-infarct area and stimulated proliferation of intrinsic neural stem/progenitor cells in the neuroproliferative zone. Conclusions-Administration

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