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Address correspondence to Hans-Willem Snoeck, The Carl C. Icahn Center for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, Box 1496, Gustave L. Levy Pl., New York, NY 10029. Phone: (212) 659-8269; Fax: (212) 803-6740; email: hans.snoeck{at}mssm.edu
Elucidation of pathways involved in mouse strain–dependent variation in the hematopoietic stem cell (HSC) compartment may reveal novel mechanisms relevant in vivo. Here, we demonstrate genetically determined variation in the proliferation of lin-Sca1++kit+ (LSK) primitive hematopoietic progenitor cells in response to transforming growth factor-ß (TGF-ß) 2, the dose response of which was biphasic with a stimulatory effect at low concentrations. In contrast, the dose responses of TGF-ß1 or -ß3 were inhibitory and did not show mouse strain–dependent variation. A quantitative trait locus (QTL) for the effect of TGF-ß2 was identified on chromosome 4 overlapping with a QTL regulating the frequency of LSK cells. These overlapping QTL were corroborated by the observation that the frequency of LSK cells is lower in adult Tgfb2+/- mice than in wild-type littermates, indicating that TGF-ß2 is a genetically determined positive regulator LSK number in vivo. Furthermore, adult Tgfb2+/- mice have a defect in competitive repopulation potential that becomes more pronounced upon serial transplantation. In fetal TGF-ß2–deficient HSCs, a defect only appears after serial reconstitution. These data suggest that TGF-ß2 can act cell autonomously and is important for HSCs that have undergone replicative stress. Thus, TGF-ß2 is a novel, genetically determined positive regulator of adult HSCs.
Key Words: growth inhibitors • immunologic and biologic factors • hematopoiesis • autocrine communication • growth and embryonic development
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