The Variation of Hematopoietic Stem Cell Self-Renewal Capacity as a Function of Age: Further Evidence for Heterogenicity of the Stem Cell Compartment

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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.