Vi. Rebel et al., Essential role for the p55 tumor necrosis factor receptor in regulating hematopoiesis at a stem cell level, J EXP MED, 190(10), 1999, pp. 1493-1503
Hematopoietic stem cell (HSC) self-renewal is a complicated process, and it
s regulatory mechanisms are poorly understood. Previous studies have identi
fied tumor necrosis factor (TNF)-alpha as a pleiotropic cytokine, which, am
ong other actions, prevents various hematopoietic progenitor cells from pro
liferating and differentiating in vitro. However, its role in regulating lo
ngterm 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 anal
yzed in a variety of hematopoietic progenitor and stem cell assays. In olde
r p55(-/-) mice (>6 mo), we identified significant differences in their hem
atopoietic system compared with age-matched p75(-/-) or wild-type counterpa
rts. Increased marrow cellularity and increased numbers of myeloid and eryt
hroid colony-forming progenitor cells (CFCs), paralleled by elevated periph
eral blood cell counts, were found in p55-deficient mice. In contrast to th
e increased myeloid compartment, pre-B CFCs were deficient in older p55(-/-
) mice. In addition, a fourfold decrease in the number of HSCs could be dem
onstrated in a competitive repopulating assay. Secondary transplantations o
f 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 reg
ulating hematopoiesis at the stem cell level.