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Blood, 15 September 2001, Vol. 98, No. 6, pp. 1782-1791
HEMATOPOIESIS
Tumor necrosis factor (TNF)-mediated activation of the p55 TNF
receptor negatively regulates maintenance of cycling reconstituting
human hematopoietic stem cells
Ingunn Dybedal,
David Bryder,
Anna Fossum,
Leiv S. Rusten, and
Sten Eirik
W. Jacobsen
From the Department of Stem Cell Biology, Institute of
Laboratory Medicine, University Hospital of Lund, Lund, Sweden, and the
Department of Oncology, The Norwegian Radium Hospital, Oslo, Norway.
Hematopoietic stem cell (HSC) fate decisions between self-renewal
and commitment toward differentiation are tightly regulated in vivo.
Recent developments in HSC culture and improvements of human HSC assays
have facilitated studies of these processes in vitro. Through such
studies stimulatory cytokines critically involved in HSC maintenance in
vivo have been demonstrated to 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 suppression. However, whether
and how TNF might affect the function of HSC with a combined myeloid
and lymphoid reconstitution potential has not been investigated. 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
lymphopoiesis in nonobese diabetic-severe combined immunodeficient
(NOD-SCID) mice. Although all cord blood and adult bone marrow
CD34+CD38 cells were capable of undergoing
cell divisions in the presence of TNF, cycling HSCs exposed to TNF in
vitro and in vivo were severely compromised in their ability to
reconstitute NOD-SCID mice and long-term cultures. The negative effect
of TNF was not dependent on the Fas pathway, and a similar effect could
be observed using a mutant TNF exclusively targeting the p55 TNF
receptor. TNF did not appear to enhance apoptosis or affect cell-cycle
distribution of cultured progenitors, but rather promoted myeloid
differentiation. Thus, TNF might regulate HSC fate by promoting their
differentiation rather than self-renewal.
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