The Positive Regulatory Effect of TGF-β2 on Primitive Murine Hemopoietic Stem and Progenitor Cells Is Dependent on Age, Genetic Background, and Serum Factors

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Abstract
TGF-β is considered a negative regulator of hemopoietic stem and progenitor cells. We have previously shown that one TGF-β isoform, TGF-β2, is, in fact, a positive regulator of murine hemopoietic stem cell function in vivo. In vitro, TGF-β2, but not TGF-β1 and TGF-β3, had a biphasic dose response on the proliferation of purified lin-Sca1++kit+ (LSK) cells, with a stimulatory effect at low concentrations, which was subject to mouse strain-dependent variation. In this study we report that the stimulatory effect of TGF-β2 on the proliferation of LSK cells increases with age and after replicative stress in C57BL/6, but not in DBA/2, mice. The age-related changes in the TGF-β2 effect correlated with life span in BXD recombinant strains. The stimulatory effect of TGF-β2 on the proliferation of LSK cells requires one or more nonprotein, low m.w. factors present in fetal calf and mouse sera. The activity of this factor(s) in mouse serum increases with age. Taken together, our data suggest a role for TGF-β2 and as yet unknown serum factors in the aging of the hemopoietic stem cell compartment and possibly in organismal aging.