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Blood, 1 September 2000, Vol. 96, No. 5, pp. 1748-1755
HEMATOPOIESIS
Interleukin-3 supports expansion of long-term multilineage
repopulating activity after multiple stem cell divisions in
vitro
David Bryder and
Sten E. W. Jacobsen
From the Stem Cell Laboratory, Institute of Laboratory
Medicine, University Hospital of Lund, Sweden.
Although long-term repopulating hematopoietic stem cells (HSC) can
self-renew and expand extensively in vivo, most efforts at expanding
HSC in vitro have proved unsuccessful and have frequently resulted in
compromised rather than improved HSC grafts. This has triggered the
search for the optimal combination of cytokines for HSC expansion.
Through such studies, c-kit ligand (KL), flt3 ligand (FL),
thrombopoietin, and IL-11 have emerged as likely positive regulators of
HSC self-renewal. In contrast, numerous studies have implicated a
unique and potent negative regulatory role of IL-3, suggesting perhaps
distinct regulation of HSC fate by different cytokines. However, the
interpretations of these findings are complicated by the fact that
different cytokines might target distinct subpopulations within the HSC
compartment and by the lack of evidence for HSC undergoing
self-renewal. Here, in the presence of KL+FL+megakaryocyte growth and
development factor (MGDF), which recruits virtually all
Lin Sca-1+kit+ bone marrow cells
into proliferation and promotes their self-renewal under serum-free
conditions, IL-3 and IL-11 revealed an indistinguishable ability to
further enhance proliferation. Surprisingly, and similar to IL-11, IL-3
supported KL+FL+MGDF-induced expansion of multilineage, long-term
reconstituting activity in primary and secondary recipients. Furthermore, high-resolution cell division tracking demonstrated that
all HSC underwent a minimum of 5 cell divisions, suggesting that
long-term repopulating HSC are not compromised by IL-3 stimulation after multiple cell divisions. In striking contrast, the ex vivo expansion of murine HSC in fetal calf serum-containing medium resulted
in extensive loss of reconstituting activity, an effect further
facilitated by the presence of IL-3.
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