Tumor necrosis factor (TNF)-mediated activation of the p55 TNF receptor negatively regulates maintenance of cycling reconstituting human hematopoietic stem cells

Hematopoietic stem cell (HSC) fate decisions between self-renewal and commi tment toward differentiation are tightly regulated in vivo. Recent developm ents in HSC culture and improvements of human HSC assays have facilitated s tudies of these processes in vitro. Through such studies stimulatory cytoki nes critically involved in HSC maintenance in vivo have been demonstrated t o also promote HSC self-renewing divisions in vitro. Evidence for negative regulators of HSC self-renewal is, however, lacking. Tumor necrosis factor (TNF), if overexpressed, has been implicated to mediate bone marrow suppres sion. However, whether and how TNF might affect the function of HSC with a combined myeloid and lymphoid reconstitution potential has not been investi gated. In the present studies in vitro conditions recently demonstrated to promote HSC self-renewing divisions in vitro were used to study the effect of TNF on human HSCs capable of reconstituting myelopoiesis and lymphopoies is in nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice. Al though all cord blood and adult bone marrow CD34(+)CD38(-) cells were capab le of undergoing cell divisions in the presence of TNF, cycling HSCs expose d to TNF in vitro and in vivo were severely compromised in their ability to reconstitute NOD-SCID mice and longterm cultures. The negative effect of T NF was not dependent on the Fas pathway, and a similar effect could be obse rved using a mutant TNF exclusively targeting the p55 TNF receptor. TNF did not appear to enhance apoptosis or affect cell-cycle distribution of cultu red progenitors, but rather promoted myeloid differentiation. Thus, TNF mig ht regulate HSC fate by promoting their differentiation rather than self-re newal. (C) 2001 by The American Society of Hematology