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

Dybedal, Ingunn; Bryder, David LU ; Fossum, Anna LU ; Rusten, Leiv S. and Jacobsen, Sten Eirik W LU (2001) In Blood 98(6). p.1782-1791
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
98
issue
6
pages
1782 - 1791
publisher
American Society of Hematology
external identifiers
  • pmid:11535512
  • scopus:0035885956
ISSN
1528-0020
DOI
10.1182/blood.V98.6.1782
language
English
LU publication?
yes
id
c3e8947b-bac6-4f28-ba35-913d11ddf620 (old id 1121574)
date added to LUP
2008-06-26 13:45:16
date last changed
2018-07-01 03:28:58
@article{c3e8947b-bac6-4f28-ba35-913d11ddf620,
  abstract     = {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.},
  author       = {Dybedal, Ingunn and Bryder, David and Fossum, Anna and Rusten, Leiv S. and Jacobsen, Sten Eirik W},
  issn         = {1528-0020},
  language     = {eng},
  number       = {6},
  pages        = {1782--1791},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Tumor necrosis factor (TNF)-mediated activation of the p55 TNF receptor negatively regulates maintenance of cycling reconstituting human hematopoietic stem cells},
  url          = {http://dx.doi.org/10.1182/blood.V98.6.1782},
  volume       = {98},
  year         = {2001},
}