Abstract
Bone marrow from wild-type mice and mice with mutated Fas (
lpr) or mutated Fas ligand (
gld) was used to investigate the role of the Fas/FasL system in the regulation of myeloid progenitor cell kinetics.
Granulocyte-macrophage colony-forming cells (CFU-GM) were measured by a standard colony assay and the proliferative activity of CFU-GM was measured by replating primary colonies and observing secondary colony formation. Fas expression was restored to
lpr mouse bone marrow cells by retrovirus-mediated gene transfer and
gld mouse marrow cells were treated with soluble FasL. Wild-type marrow cells were treated with YVAD (a caspase inhibitor) or anti-Fas monoclonal antibodies.
There were greater frequencies of myeloid progenitor cells (CFU-GM) in
lpr and
gld mouse marrow compared to wild-type (WT) marrow
(p
= 0.0008)
. The proliferative capacity of CFU-GM was also significantly greater for
lpr and
gld CFU-GM compared to WT CFU-GM
(p
= 0.0003
and 0.0001,
respectively)
. Retrovirus-mediated restoration of Fas into
lpr marrow, and provision of soluble FasL (sFasL) to
gld CFU-GM reduced CFU-GM proliferation to WT levels. Treatment of WT CFU-GM with YVAD or anti-FasL monoclonal antibody increased CFU-GM proliferation to the levels found in
lpr and
gld CFU-GM. YVAD significantly increased and anti-Fas significantly reduced the proliferative capacity of human CFU-GM
(p
= 0.015
and 0.04,
respectively)
.
Fas, FasL, and caspase activation may play an important role in regulating myeloid progenitor cell kinetics.