Synchronized Cell-Cycle Induction of Engrafting Long-Term Repopulating Stem Cells

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Abstract
We have recently defined the window for marrow stem cell homing into nonablated hosts as the first 24 hours posttransplant. Within this homing window, donor cells rapidly cleared from the peripheral blood and lungs and plateaued in the marrow. We have now assessed the cell-cycle status of the engrafting cells capable of contributing to long-term hematopoiesis using administration of hydroxyurea (HU), a chemotherapy agent with S-phase cell-cycle specificity. HU was given at very short periods following a male bone marrow transplant (0, 3, 6, 12, and 15 hours) into female nonablated hosts, and donor cell engraftment was analyzed after 6 weeks. The data show that quickly after transplant (12 hours), greater than half of the engrafting cells capable of contributing long-term to all levels of the hematopoietic hierarchy are in S-phase. Analysis after 6 weeks included whole bone marrow, peripheral blood, primitive cells with high proliferative potential, and mature lineage-restricted marrow cells. These donor cells appear to be naturally synchronized. When HU was administered at any of the other time points, there was little evidence of cell death 6 weeks postengraftment.