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PMID: 10562323 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Essential role for the p55 tumor necrosis factor receptor in regulating hematopoiesis at a stem cell level.

The Journal of experimental medicine ·Vol. 190 ·No. 10 ·1999-11-15 ·Pages 1493-504

Rebel VI, Hartnett S, Hill GR, Lazo-Kallanian SB, Ferrara JL, Sieff CA

Abstract

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)-alpha 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.

MeSH Terms
Animals Antigens, CD/physiology Cell Cycle Cell Division Hematopoiesis Hematopoietic Stem Cells/physiology Mice Mice, Inbred C57BL Mice, Knockout Receptors, Tumor Necrosis Factor/physiology Receptors, Tumor Necrosis Factor, Type I Receptors, Tumor Necrosis Factor, Type II
Chemicals
Antigens, CD Receptors, Tumor Necrosis Factor Receptors, Tumor Necrosis Factor, Type I Receptors, Tumor Necrosis Factor, Type II
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Rebel V I
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. vivienne_rebel@dfci.harvard.edu
Hartnett S
Hill G R
Lazo-Kallanian S B
Ferrara J L
Sieff C A
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.190.10.1493
Email
vivienne_rebel@dfci.harvard.edu
Published
1999-11-15
Pages
1493-504
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2195701
Subset
IM
Grants
NCI NIH HHS · P01 CA39542 · United States
NHLBI NIH HHS · R01 HL55709 · United States
External Links
PubMed source DOI: 10.1084/jem.190.10.1493 PMC Full Text View journal details
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