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Soluble factor(s) produced by human bone marrow stroma increase
cytokine-induced proliferation and maturation of primitive hematopoietic
progenitors while preventing their terminal differentiation
CM Verfaillie
Department of Medicine, University of Minnesota, Minneapolis.
We have recently shown that conservation and differentiation of primitive
human hematopoietic progenitors in in vitro long-term bone marrow cultures
(LTBMC) occurs to a greater extent when hematopoietic cells are grown
separated from the stromal layer than when grown in direct contact with the
stroma. This finding suggests that hematopoiesis may depend mainly on
soluble factors produced by the stroma. To define these soluble factors, we
examine here whether a combination of defined early-acting cytokines can
replace soluble stroma-derived biologic activities that induce conservation
and differentiation of primitive progenitors. Normal human Lineage-
/CD34+/HLA-DR- cells (DR-) were cultured either in the absence of a stromal
layer ("stroma-free") or in a culture system in which DR- cells were
separated from the stromal layer by a microporous membrane
("stroma-noncontact"). Both culture systems were supplemented three times
per week with or without cytokines. These studies show that culture of DR-
cells for 5 weeks in a "stroma-free" culture supplemented with a
combination of four early acting cytokines (Interleukin-3 [IL-3], stem cell
factor [SCF], leukemia-inhibitory factor [LIF], and granulocyte
colony-stimulating factor [G-CSF]) results in a similar cell expansion as
when DR- cells are cultured in "stroma-noncontact" cultures supplemented
with the same cytokines. However, generation of committed progenitors and
conservation of the more primitive long-term bone marrow culture initiating
cells (LTBMC- IC) was far superior in "stroma-noncontact" cultures
supplemented with or without IL-3 than in "stroma-free" cultures
supplemented with IL-3 alone or a combination of IL-3, LIF, G-CSF, and SCF.
These studies indicate that human BM stroma produces soluble factors that
can either alone or in synergy with defined cytokines (1) conserve
primitive LTBMC- IC, (2) induce early differentiation of a fraction of the
primitive progenitors, and (3) prevent their terminal differentiation. We
show here that these stroma-derived factors are not likely to be the known
early acting cytokines IL-3, SCF, LIF, or G-CSF. Characterization of the
stroma-derived factor(s) may have important implications for clinically
relevant studies, such as in vitro stem cell expansion in cancer treatment
and gene therapy.
Volume 82,
Issue 7,
pp. 2045-2053,
10/01/1993
Copyright © 1993 by The American Society of Hematology
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