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Original Article |
vivienne_rebel{at}dfci.harvard.edu
Hematopoietic stem cell (HSC) self-renewal is a complicated process, and its regulatory mechanisms are poorly understood. Previous studies have identified tumor necrosis factor (TNF)-
as a pleiotropic cytokine, which, among other actions, prevents various hematopoietic progenitor cells from proliferating and differentiating in vitro. However, its role in regulating long-term repopulating HSCs in vivo has not been investigated. In this study, mice deficient for the p55 or the p75 subunit of the TNF receptor were analyzed in a variety of hematopoietic progenitor and stem cell assays. In older p55–/– mice (>6 mo), we identified significant differences in their hematopoietic system compared with age-matched p75–/– or wild-type counterparts. Increased marrow cellularity and increased numbers of myeloid and erythroid colony-forming progenitor cells (CFCs), paralleled by elevated peripheral blood cell counts, were found in p55-deficient mice. In contrast to the increased myeloid compartment, pre-B CFCs were deficient in older p55–/– mice. In addition, a fourfold decrease in the number of HSCs could be demonstrated in a competitive repopulating assay. Secondary transplantations of marrow cells from primary recipients of p55–/– marrow revealed impaired self-renewal ability of p55-deficient HSCs. These data show that, in vivo, signaling through the p55 subunit of the TNF receptor is essential for regulating hematopoiesis at the stem cell level.
Key Words: hematopoietic stem cell cell differentiation cytokine receptors
Abbreviations used in this paper: BFU-E, erythroid burst-forming unit; BM, bone marrow; CFC, colony-forming cell; CFU-GEMM, multilineage CFU; CFU-G/M, granulocyte/macrophage CFU; CFU-S, CFU in the spleen; CRU, competitive repopulating unit(s); HSC, hematopoietic stem cell; Lin, lineage; PB, peripheral blood; PI, propidium iodide; SSC, side scatter; WBC, white blood cell; WT, wild-type.
J.L.M. Ferrara and C.A. Sieff contributed equally to this paper.
© 1999 The Rockefeller University Press
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