Optimizing hematopoietic recovery following bone marrow transplantation.

Blood cell production is a dynamic process in which immature precursors progress through a series of developmental events that culminate in the production of mature cells of the erythroid, myeloid, and lymphoid lineages. The characteristics of cells at particular stages of development and the intrinsic and extrinsic signals that regulate their growth and differentiation are becoming increasingly well defined. As a result, it is now possible to orient them in the hierarchical model shown in Figure 1 (1). At the head of this schema is the pluripotent hematopoietic stem cell (PHSC), which can self-renew and generate differentiated progeny (2). In both humans and mice, PHSCs lack cell surface determinants expressed by committed myeloid and lymphoid lineage cells. Further resolution of this lineage-negative population based on the expression of Thy-1 and Sca-1 in the mouse (3) and CD34 in humans (4) has allowed PHSCs to be isolated from the bone marrow. This achievement, made possible by advances in mAb production and flow cytometry, is remarkable because PHSCs account for only 0.05–0.1% of total bone marrow nucleated cells. PHSC progeny can also be purified from murine bone marrow based on their phenotypic characteristics. These include the common lymphoid progenitor (CLP), from which B, T, and natural killer cells descend, and the common myeloid progenitor (CMP), from which all myeloid and erythroid cells are derived (5, 6). That the populations designated as PHSCs, CMPs, and CLPs have the developmental potential ascribed to them was determined prospectively: Cells expressing particular phenotypes were isolated, and their ability to generate various hematopoietic lineages was determined in vitro and in vivo. These types of reconstitution studies revealed that only PHSCs can mediate stable, long-term hematopoietic repopulation of recipients; more differentiated progenitors provide transient reconstitution. The ability to isolate and transplant PHSCs has a number of clinical advantages. For example, one complication following allogeneic bone marrow transplantation is T cell–mediated graft-versushost disease. Transplantation of PHSC-enriched, T cell–depleted donor cells might mitigate the chances of its occurrence. It is also now possible to consider the transplantation of PHSCs in which exogenous genes have been introduced to correct genetic defects. One disadvantage of using purified PHSCs alone to reconstitute hematopoiesis is clear. Mice that have received myeloablative radiation often die 2–3 weeks after PHSC transplantation, because these cells require additional time to proliferate and differentiate into mature peripheral blood cells. In the interim, the mice are neutropenic, thrombocytopenic, and anemic. Experimental Commentary