Supportive Role of TNF-Family Death Receptors in Hematopoietic Cell Engraftment.

The activity of death receptors of the tumor necrosis factor (TNF) superfamily as negative regulators of distal differentiation in the immuno-hematopoietic system is well characterized. The role of these receptors, classically associated with transduction of apoptotic signals, is unknown. A series of studies have attributed these receptors also negative regulatory functions in ex vivo expanded hematopoietic progenitors, showing variable supporting and suppressive interactions with growth factors. We observed robust upregulation of Fas, TNF-R1, TNF-R2 and TRAIL-R2 in bone marrow homed donor cells, reaching levels of 60–75% expression after 6 days. All putative SCA-1⁺c-kit⁺lin⁻ progenitors ubiquitously expressed all four receptors. These receptor-positive cells were largely resistant to apoptotic signals delivered by the corresponding soluble and membranous ligands. Furthermore, there was no evidence of receptor cross-talk in sensitization of the cells to apoptotic death. The engraftment potential of cells was markedly diminished by ex vivo incubation, without any relationship to the viability of the putative progenitors. Taken together these data suggest a supportive role of the “death receptors” in hematopoietic cell engraftment and dissociate the deficient engraftment of cultured cells from apoptosis of progenitors.