Dynamic changes in mouse hematopoietic stem cell numbers during aging

To address the fundamental question of whether or not stem cell populations age, we performed quantitative measurements of the cycling status and freq uency of hematopoietic stem cells in long-lived C57BL/6 (B6) and short-live d DBA/2 (DBA) mice at different developmental and aging stages. The frequen cy of cobblestone area-forming cells (CAFC) day-35 in DBA fetal liver was t wofold to threefold higher than in B6 mice, and by late gestation, the tota l stem cell number was nearly as large as that of young DBA adults. Followi ng a further approximate to 50% increase in stem cells between 6 weeks and 1 year of age, numbers in old DBA mice dropped precipitously between 12 and 20 months of age. In marked contrast, this stem cell population in B6 mice increased at a constant rate from late gestation to 20 months of age with no signs of abatement, Throughout development an inverse correlation was ob served between stem cell numbers and the percentage of cells in S-phase. Be cause a strong genetic component contributed to the changes in stem cell nu mbers during aging, we quantified stem cells of 20-month old BXD recombinan t inbred (RI) mice, derived from B6 and DBA progenitor strains, thus permit ting detailed Interstrain genetic analysis. For each BXD strain we calculat ed the stem cell increase or decrease as mice aged from 2 to 20 months. Net changes in CAFC-day 35 numbers among BXD strains ranged from an approximat e to 10-fold decrease to an approximate to 10-fold increase. A genome wide search for loci associated with this quantitative trait was performed. Seve ral loci contribute to the trait-putative loci map to chromosomes X, 2, and 14. We conclude that stem cell numbers fluctuate widely during aging and t hat this has a strong genetic basis. (C) 1999 by The American Society of He matology.