Quantitative trait analysis reveals transforming growth factor-beta2 as a positive regulator of early hematopoietic progenitor and stem cell function.
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-beta (TGF-beta) 2, the dose response of which was biphasic with a stimulatory effect at low concentrations. In contrast, the dose responses of TGF-beta1 or -beta3 were inhibitory and did not show mouse strain-dependent variation. A quantitative trait locus (QTL) for the effect of TGF-beta2 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-beta2 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-beta2-deficient HSCs, a defect only appears after serial reconstitution. These data suggest that TGF-beta2 can act cell autonomously and is important for HSCs that have undergone replicative stress. Thus, TGF-beta2 is a novel, genetically determined positive regulator of adult HSCs.
Langer
Jessica C
JC
The Carl C. Icahn Center for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, Box 1496, Gustave L. Levy Place, New York, NY 10029, USA.
Henckaerts
Els
E
Orenstein
Jonathan
J
Snoeck
Hans-Willem
HW
D000818:Animals; D002874:Chromosome Mapping; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology; D008099:Liver / Q000166:cytology / Q000196:embryology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D040641:Quantitative Trait Loci / Q000235:genetics*; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D053781:Transforming Growth Factor beta2
D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2