Evidence for structured variation in self-renewal capacity within long-term bone marrow cultures.

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Abstract
Bone marrow pluripotent stem cells (CFUs) demonstrate capacity for proliferation and differentiation. The proliferative capacity of CFUs was measured by serial transplantability and by the Rs, a measurement of CFU production in a single, 14-day transfer. In the present study, the self-renewal capacity of adherent and nonadherent [mouse] CFUs from long-term bone marrow cultures was measured. Culture conditions were established such that nonadherent cells were derived from the adherent cell layer. Adherent and nonadherent cells produced spleen colonies, demonstrating that significant proliferative potential was present in both locations; however, at all times in culture, the CFUs within the adherent stromal cell layer had a significantly greater self-renewal capacity than did the nonadherent CFUs. During the initial establishment of the cultures, the self-renewal capacity of the adherent CFUs decreased as the total number of CFUs per flask increased. After 3 wk in culture, the self-renewal potential of the adherent CFUs stabilized and was maintained. The results suggest 2 different mechanisms of stem cell proliferation. To increase the most primitive stem cell pool size, there was initial proliferation of early stem cells with a concomitant decrease in self-renewal capacity. Once this pool was established, the self-renewal capacity of the adherent CFUs maintained for 13 wk in culture suggests that CFU production and cell maintenance were achieved by clonal succession.