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a Centre de Recherches du Service de
Santé des Armées, La Tronche, France;
b Institut Albert Bonniot, La Tronche,
France
Key Words. Apoptosis • Fas • CD34+ cells • Irradiation • Cytokines • Ex vivo expansion
Dr. Michel Drouet, Experimental Radiohematology Unit, CRSSA, 24, avenue des Maquis du Grésivaudan BP 87-38702 La Tronche Cedex, France.
Recovery from radiation-induced (RI) bone marrow aplasia depends
on appropriate cytokine support. The early effects of exogenous
cytokines at the hematopoietic stem and progenitor cell (HSPC) level
following irradiation are still largely unknown, especially those of
survival factors such as stem cell factor (SCF) and Flt-3 ligand
(FL). This study was aimed at A) clarifying Fas/Fas-Ligand (Fas-L)
implication in RI apoptosis of CD34+ cells and B) assessing
the capacity of a combination of cytokines to mitigate RI apoptosis in
HSPCs in vitro. We showed that most of in vitro gamma-irradiated
CD34+ HSPCs incubated in a medium devoid of cytokines
underwent progressive apoptosis-related changes from 6 h (i.e.,
decreased CD34 antigen expression, Annexin V binding); then Fas/Fas-L
coexpression occurred from 10 h on. A strong DNA fragmentation, as
assessed by TUNEL assay and propidium iodide staining, was observed at
24 h. Within a 2.5- to 6-Gy dose range, the RI apoptotic process
finally led to 97% CD34+ cell death within 48 h with a
complete loss of functionality. Unirradiated cells incubated in the
same conditions displayed a significantly reduced apoptotic
pattern. The early addition of a combination of SCF, FL,
thrombopoietin, and interleukin 3 (4F) after cell irradiation
prevented 15% (2.5 Gy) and 12% (4 Gy) of HSPCs, respectively, from RI
apoptosis, whereas these cytokines used as single factors were
inefficient. Furthermore, irradiated HSPCs (2.5 Gy) incubated with 4F
in a serum-free culture system for seven days proliferated, giving
rise to an increase in the number of total cells (x 5.6-fold)
and CD34+ cells (x 4.2-fold) and to megakaryocytic
and granulomonocytic precursors. These results show that the
prevention of apoptosis in in vitro irradiated HSPCs depends on an
early combination cytokine support. These data suggest that the early
therapeutic administration of anti-apoptotic cytokines may be critical
for preserving functional HSPCs from in vivo radiation
damage.
This article has been cited by other articles:
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  M. Drouet, F. Mourcin, N. Grenier, V. Leroux, J. Denis, J.-F. Mayol, P. Thullier, J.-J. Lataillade, and F. Herodin Single administration of stem cell factor, FLT-3 ligand, megakaryocyte growth and development factor, and interleukin-3 in combination soon after irradiation prevents nonhuman primates from myelosuppression: long-term follow-up of hematopoiesis Blood, February 1, 2004; 103(3): 878 - 885. [Abstract] [Full Text] [PDF]
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F. Herodin, P. Bourin, J.-F. Mayol, J.-J. Lataillade, and M. Drouet Short-term injection of antiapoptotic cytokine combinations soon after lethal gamma -irradiation promotes survival Blood, April 1, 2003; 101(7): 2609 - 2616. [Abstract] [Full Text] [PDF]
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 M. Drouet, F. Herodin, F. Norol, F. Mourcin, and J.F. Mayol Cell Cycle Activation of Peripheral Blood Stem and Progenitor Cells Expanded Ex Vivo with SCF, FLT-3 Ligand, TPO, and IL-3 Results in Accelerated Granulocyte Recovery in a Baboon Model of Autologous Transplantation but G0/G1 and S/G2/M Graft Cell Content Does Not Correlate with Tranplantability Stem Cells, September 1, 2001; 19(5): 436 - 442. [Abstract] [Full Text] [PDF]
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