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Blood, Vol. 93 No. 10 (May 15), 1999:
pp. 3294-3301
Dynamic Changes in Mouse Hematopoietic Stem Cell Numbers During Aging
Gerald de Haan and
Gary Van Zant
From the Blood and Marrow Transplant Program, Division of
Hematology/Oncology, University of Kentucky, Markey Cancer Center,
Lexington, KY; and the Department of Physiological Chemistry,
University of Groningen, Groningen, the Netherlands.
To address the fundamental question of whether or not stem cell
populations age, we performed quantitative measurements of the cycling
status and frequency of hematopoietic stem cells in long-lived C57BL/6
(B6) and short-lived DBA/2 (DBA) mice at different developmental and
aging stages. The frequency of cobblestone area-forming cells (CAFC)
day-35 in DBA fetal liver was twofold to threefold higher than in B6
mice, and by late gestation, the total stem cell number was nearly as
large as that of young DBA adults. Following a further  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 observed
between stem cell numbers and the percentage of cells in S-phase.
Because a strong genetic component contributed to the changes in stem
cell numbers during aging, we quantified stem cells of 20-month old BXD
recombinant inbred (RI) mice, derived from B6 and DBA progenitor
strains, thus permitting detailed interstrain genetic analysis. For
each BXD strain we calculated 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 10-fold decrease to an 10-fold increase. A genome-wide search for loci associated with this
quantitative trait was performed. Several 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 that this has a
strong genetic basis.
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