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Effects of interleukin-3 and c-kit ligand on the survival of various
classes of human hematopoietic progenitor cells
JE Brandt, K Bhalla and R Hoffman
Hematology-Oncology Section, Indiana University School of Medicine,
Indianapolis.
We examined the effects of interleukin-3 (IL-3) and c-kit ligand (KL) on
the survival of differentiated hematopoietic progenitor cells (HPC), the
burst-forming unit-erythroid (BFU-E); colony-forming unit- granulocyte,
erythroid, monocyte, megakaryocyte (CFU-GEMM); and CFU-
granulocyte-monocyte (CFU-GM) and more primitive hematopoietic cells that
give rise to these progenitor cells (pre-colony-forming cells [pre- CFC]).
CD34+ HLA-DR+ cells, which are highly enriched for committed HPC, and CD34+
HLA-DR- c-kit+ cells, which contain the most primitive assayable
hematopoietic cells, including long-term bone marrow culture- initiating
cells, high proliferative potential-CFC, the CFU-blast, and the
BFU-megakaryocyte, were suspended in serum-free medium in the presence or
absence of IL-3 or KL. CD34+ HLA-DR+ cells incubated under serum-free
conditions or in the presence of KL for 96 hours lost greater than 90% of
assayable unilineage or multilineage HPC, whereas those cells incubated in
the presence of IL-3 retained 40% of the number of HPC present at time 0.
The effect of IL-3 on HPC survival was most pronounced on the BFU-E and
CFU-GEMM present within CD34+ HLA-DR+ cells. Addition of IL-3, but not of
KL, to CD34+ HLA-DR+ cells delayed the appearance of morphologic changes
and DNA fragmentation patterns associated with cell death occurring by
apoptosis. CD34+ HLA-DR-c-kit+ cells were incubated under similar
serum-free conditions in the presence or absence of IL-3 or KL, and the
frequency of pre-CFC was determined by limiting dilution analysis. The
frequency of pre-CFC in cells incubated for 48 hours in the absence of
serum was similar to that of cells incubated in the presence of IL-3 and
approximately doubled when CD34+ HLA-DR- c-kit+ cells were incubated in the
presence of KL. Addition of KL to serum-free suspension cultures of CD34+
HLA-DR- c-kit+ cells delayed the appearance of DNA fragmentation patterns
associated with apoptosis to a greater extent than did the addition of
IL-3. These studies suggests that IL-3, but not KL, promotes HPC survival,
whereas KL plays a greater role than IL-3 in sustaining more primitive HPC,
such as pre-CFC. The effects of both cytokines in mediating HPC and
primitive hematopoietic cell survival appear to be related, in part, to
their ability to suppress apoptosis.
Volume 83,
Issue 6,
pp. 1507-1514,
03/15/1994
Copyright © 1994 by The American Society of Hematology
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