Long-term hematopoietic damage: concepts, approaches, and results relevant to the study of environmental toxins.

The hematopoietic tissue is one of the prime examples of hierarchical tissues, where mature cells with a limited life span are continually replaced as a result of proliferation and differentiation from stem and progenitor cells. In the bone marrow, these processes are controlled by growth factors and by cell to cell interactions, the latter being specially important for the regulation of the stem-cell population. In the study of long-term hematopoietic damage, we have to distinguish between deleterious effects of the environmental toxins on the stem and progenitor cells, and on the stromal bone marrow cells which are part of the regulatory hematopoietic microenvironment. In some experimental situations, the function of the tissue may be subnormal, not because of stem cell damage (which may also be present), but because of damage to regulatory environmental populations. Because of the high degree of organization of the hematopoietic tissue (not immediately obvious from histological sections), the heterogeneity of the stromal cell populations, and their different capacities to regenerate after cytotoxic insult, the stromal damage is likely to be heterogeneous and would tend to be expressed functionally at later times than acute hematopoietic injury. While microenvironmental damage may be of importance in the induction of hematopoietic failure, the primary target in leukemogenesis is likely to be the stem cell. However, experimental data support the concept that regulatory microenvironmental influences may hinder or favor the development of leukemia.