Regulation and reconstitution of human hematopoiesis

Hematopoiesis is regulated by complex interactions between hematopoietic cells and stromal cells within the bone marrow microenvironment. The stromal cells of this microenvironment secrete hematopoietic factors, produce extracellular matrix and mediate direct cell-to-cell contact; each of these events provides a basis for regulatory control of hematopoiesis. With advances in cell surface phenotyping and cell separation technology, it has been shown that the CD34+CD38-CD45RAlowCD71low population contains hematopoietic stem cells. Most hematopoietic stem cells are in a quiescent, noncycling state (G0). In response to external signals, however, they can rapidly enter a functional state (G1) in preparation for DNA synthesis (S-phase). There have been high expectations, recently, that stimulatory hematopoietic factors will have an important impact on chemotherapy by reducing drug-induced neutropenia and, thereby, allowing dose-intensification of treatment. Similar clinical benefits, however, could also be realized by protecting hematopoietic cells from the cytotoxicity of cycle-specific chemotherapeutic agents by blocking the entrance of the hematopoietic stem cells into the cell cycle. Recent studies have suggested that the addition of a negative regulator can better maintain hematopoiesis in vitro and that cells capable of long-term engraftment are primarily comprised of a noncycling population. On the other hand, exposure to cycling-promoting cytokines ex vivo may produce an "engraftment defect". An hu-SCID murine model with a high degree of human cell engraftment will be useful for future studies of the in vivo effects of various agents, infections or gene therapy on human hematopoiesis.