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Characterization of a bipotent erythro-megakaryocytic progenitor in human
bone marrow
N Debili, L Coulombel, L Croisille, A Katz, J Guichard, J Breton-Gorius and W Vainchenker
INSERM U362, Institut Gustave Roussy, Villejuif, France.
The aim of the present study was to determine if the human erythroid (E)
and megakaryocytic (MK) lineages were closely linked to the existence of a
bipotent burst-forming unit (BFU) E/MK progenitor. In methylcellulose
cultures, BFU-E/MK colonies were observed at day 12 and closely resembled
mature BFU-E with the exception that the erythroid component was surrounded
by MK. These colonies were quite different from the colony forming unit
(CFU)-GEMM-derived colonies, which were composed of a larger number of
erythroblasts and which developed later in culture. The existence of these
bilineage colonies composed of 100 to 1,000 erythroblasts intermingled with
a few MK and without granulocytic cells was confirmed by the plasma clot
technique and immunoalkaline phosphatase labeling of the MK. To investigate
if this bipotent progenitor belonged to the compartment of primitive
progenitors, CD34+ marrow cells were subfractionated according to
expression of the CD38 antigen. The bipotent BFU-E/MK progenitor as well as
a large fraction of MK progenitors were found in the CD34+ CD38+/- or in
the CD34+ CD38- cell fractions. Growth of this bipotent BFU-E/MK progenitor
required the combination of stem cell factor (SCF), Interleukin-3 (IL-3),
and Epo in serum free conditions. Addition of IL- 6 had only a marginal
effect, whereas megakaryocyte growth and development factor (MGDF) was not
an absolute requirement, but slightly increased the plating efficiency of
CFU-MK and of BFU-E/MK progenitors when combined with SCF, IL-3, and Epo.
In contrast, when these cultures were performed in the presence of 30%
fetal calf serum, no BFU-E/MK colonies were observed irrespective of the
combination of growth factors used, including the presence of MGDF;
however, inclusion of the MS-5 cell line restored the growth of this
bipotent progenitor. In contrast, in cultures performed in the presence of
human normal or aplastic plasma, MS-5 had only a slight effect on the
cloning efficiency but improved MK cytoplasmic maturation and MK size,
suggesting that the main effect of MS-5 is to diminish the inhibitory
effect of the fetal calf serum on the MK differentiation. The clonal origin
of bipotent BFU-E/MK colonies was demonstrated in liquid culture of single
CD34+ CD38low cells by immunophenotyping individual clones. At day 12, 30%
of the clones contained erythroblasts (glycophorin A+) and some MK (CD41+)
without granulocytes (G) or macrophages (M) (CD14+ and CD15+). At day 20,
clones containing erythroblasts and MK were rare (5%). In contrast
multilineage clones could be frequently detected at this time without
passage from BFU-E/MK clones at day 12 to GEMM at day 20. These results
suggest that a bipotent BFU-E/MK progenitor may be a nonrandom step in the
hierarchical development of stem cells.
Volume 88,
Issue 4,
pp. 1284-1296,
08/15/1996
Copyright © 1996 by The American Society of Hematology
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