Hematopoietic stem cell regulatory volumes as revealed in studies of the bgj/bgj:W/WV chimera.

ABSTRACT

The kinetics of bone marrow replacement was studied in W/WV mice implanted with gbj/bgj (beige) stem cells, with the characteristic beige neutrophil marker as a criterion of the takeover of host marrow by donor marrow. A hyperbolic pattern of W/WV marrow replacement conforming to a log dose-response was observed in experiments encompassing a 50-fold range of bgj/bgj inoculum doses and a 2-yr period of observation. The dose-response relationships were consistent with random seeding of stem cells in the host marrow coupled with a decreasing efficiency of secondary colonization by local migration. Application of single-hit Poisson sampling statistics to the dose-response data led to the hypothesis that mouse bone marrow is compartmentalized into essentially self-contained stem cell regulatory volumes or domains. We estimate that W/WV marrow contains about 2,600 stem cells regulatory units with an average volume of about 10(8) micron3, a dimension consistent with the presumptive role of short-range cell-cell interactions in the regulation of pluripotent stem cells. Our analysis of the dose-response data is also indicative of the discontinuous and limited nature of local stem cell migration in a cellular marrow, a consideration that may be of practical as well as theoretical interest.