Nonlinear effects of radiation dose on donor-cell reconstitution by limited numbers of purified stem cells.

ABSTRACT

Despite the increasing use of bone marrow transplantation (BMT) as a treatment for a wide variety of diseases, the numbers and types of cells required for both rapid and sustained recovery of hematopoiesis are not well defined. To investigate further the potential of transplants consisting of highly enriched populations of long-term repopulating cells, we transplanted a series of Ly-5.2 mice given various doses (750, 800, 850, 900, or 950 cGy) of total-body irradiation (TBI) with 30 or 90 Sca-1+Lin-WGA+ marrow cells isolated from congenic Ly-5.1 donors. As expected, mature progeny derived from these cells, belonging to both myeloid and lymphoid compartments, could be detected with increasing case in recipients given radiation doses from 750 to 900 cGy TBI. Surprisingly, expression of this potential was significantly reduced in mice that had received 950 cGy TBI. This contrasts with the capacity of the same number of purified Sca-1+Lin-WGA+ cells to generate readily detectable progeny in 950 cGy treated mice given a simultaneous transplant of 10(5) normal marrow cells or 2 x 10(5) serially passaged marrow cells. We suggest that this variable behavior of purified stem cells in differently treated recipients may reflect radiation dose-dependent differences in the types or levels of expression of factors that regulate transplanted stem cell proliferation and differentiation in vivo and that above a certain threshold radiation dose, this may result in an irreversible loss of long-term reconstituting potential. Regardless of the nature of the underlying mechanism, this study shows that the extent of donor repopulation after BMT can be a function not only of the number of stem cells transplanted but also of the conditioning of the recipient and whether other cell types are also injected.