Life Span of Multipotential Hematopoietic

The hematopoietic system is maintained throughout adult life by a population of immature precursors known as the multipotential stem cells . These stem cells are unique within the system in that they have the capacity to generate progeny of all the blood cell lineages, as well as the capacity to generate cells with a potential similar to their own, a characteristic often referred to as self-renewal (1-8). It is this self-renewal capacity that enables stem cells to give rise to functional blood cells over long periods of time in an unperturbed hematopoietic system or to generate a new blood cell system when transplanted to hematopoietically deficient recipients . Although these characteristics of stem cells have been recognized for some time, it is still not known to what extent stem cells can self-renew. If this capacity is unlimited, then stem cells should be "immortal" and able to function for an entire lifetime. If this is true, then the clonal make-up of the hematopoietic system should remain relatively stable over extended periods of time . On the other hand, if the self-renewal capacity of the stem cell is limited, then these cells would have a finite life span . Under this latter condition only a portion of the total stem cell pool would be active at a given time, and new stem cells would be drawn from this pool to replace those that are dying . This constant turnover in the active stem cell population would lead to a change, with time, in the clonal make-up of the different hematopoietic lineages . Hematopoiesis then would be maintained by a succession of shortlived clones as was proposed by the clonal succession model of Kay (9) . A number of studies (6, 8, 10, 11) have demonstrated that the hematopoietic system of an irradiated reconstituted mouse does in fact undergo some clonal changes with time and thus would support the concept of short-lived stem cells . Experiments from several other groups, however, have provided evidence indicating that at least a subpopulation of stem cells are long-lived, able to function for significant periods of time (7, 12-14) . One approach that has been used to address this issue is to uniquely mark stem cells through the use of retroviral integration sites and then follow the fate of their progeny when introduced into recipient mice (6, 7, 11) . In a previous report (7) we analyzed the clonal make-up of the various hematopoietic lineages ofsuch recipients