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There is substantial evidence for limited proliferative capacity of the hematopoietic progenitors. Hematopoiesis in mice is maintained by primitive stem cells that are assayed by their ability to form spleen colonies (CFU-S). To measure the average proliferative capacity of these cells (CFU-S), bone marrow containing 50-150 CFU-S is injected into lethally irradiated mice, and 14 days later, the number present in the recipient marrow is measured. In fetal life between 13 and 16 days of gestation, the hematopoietic stem cells are primarily localized in the liver. There is a decrease in the average proliferative capacity of these stem cells as they progress from fetal life into adulthood. This proliferative capacity of these significantly increases in late adulthood. However, if one scores maximum self-renewal or proliferative capacity by another assay consisting of the serial transplantation of marrow at 14-day intervals, this capacity is unchanged with age. These observations can be explained by considering the stem cell compartment as a continuum of cells whose self-renewal capacity varies inversely with their divisional history. All stem cells participate in repopulation when the pool needs rapid expansion (fetal life). During steady-state repopulation (adult life), clones are selected on the basis of their divisional history, those with the greatest proliferative history being selected. Thus, the average proliferative capacity of the remaining stem cells will increase as the adult animal ages, since stem cells of low proliferative potential have been consumed. The maximal self-renewal capacity will remain unchanged, since this measures the spared earliest cells with the highest proliferative capacity.

Bone marrow from old (greater than 2 yr of age) and young (8-10 wk of age) male C3H/HeJ mice was grown in long-term bone marrow cultures and assayed for weekly hematopoietic stem cell (CFUs) production and interval serf-renewal capacity (Rs). Greater numbers of CFUs were noted in old marrow as compared to young marrow cultures over the first 4 wk duration, but subsequently, greater numbers of CFUs were seen weekly in the young marrow cultures. Over 13 wk in culture, the total CFUs determination was greater in young marrow cultures. Similarly, self-renewal capacity (Rs) was greater in old as compared to young marrow-adherent CFUs over the first 4-5 wk, but subsequently, young marrow CFUs had a greater self-renewal. In an attempt to separately study stroma from hematopoietic cells, old and young hematopoietic cells were grown on old and young stroma. The differences seen between old and young marrow cultures over the first 4-5 wk appeared related to the age of the hematopoietic cells overlayed and were independent of the age of the stroma. However, after 4 wk, the young marrow stroma appeared to have a rejuvenating effect on the old marrow hematopoietic cell overlays. These results support the notion that bone marrow has a limited proliferative capacity. Old marrow grown in long-term bone marrow culture has a total decreased CFUs production and an early decline in self-renewal capacity as compared to young marrow. The initial high self-renewal capacity noted in old marrow cultures over the first 4 wk may reflect selective utilization in vivo of CFUs with a lower mean self-renewal to maintain hematopoiesis.