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Blood, Vol. 94 No. 3 (August 1), 1999:
pp. 923-931
The Soluble Interleukin-6 (IL-6) Receptor/IL-6 Fusion Protein Enhances
In Vitro Maintenance and Proliferation of Human
CD34+CD38 /low Cells Capable of
Repopulating Severe Combined Immunodeficiency Mice
Orit Kollet,
Ronit Aviram,
Judith Chebath,
Herzl ben-Hur,
Arnon Nagler,
Leonard Shultz,
Michel Revel, and
Tsvee Lapidot
From the Departments of Immunology and of Molecular Genetics, The
Weizmann Institute of Science, Rehovot, Israel; the Department of
Obstetrics and Gynecology, Kaplan Hospital, Rehovot, Israel; the
Department of Bone Marrow Transplantation, Hadassah University
Hospital, Jerusalem, Israel; and The Jackson Laboratory, Bar
Harbor, ME.
In vitro maintenance and proliferation of human hematopoietic stem
cells is crucial for many clinical applications. Early hematopoietic
cells express low levels of FLT-3 and c-kit receptors, as well as the
interleukin-6 (IL-6) receptor signal transducing element, gp130, but do
not express IL-6 receptor itself. Therefore, we have attempted to
maintain human cord blood or bone marrow CD34+ cells ex
vivo in serum-free cultures containing stem cell factor (SCF) and FLT-3
ligand (FL) alone or together with a new recombinant molecule of
soluble IL-6 receptor fused to IL-6 (IL6RIL6 chimera). The effect of
IL6RIL6 chimera on the proliferation and differentiation of
CD34+ cells was compared with that of each chimera
component added separately. The engraftment potential of in
vitro-cultured cells was determined using our recently established
functional in vivo assay for primitive human severe combined
immunodeficiency (SCID)-repopulating cells (SRC). We
report here that IL6RIL6 chimera induced significantly higher levels of
progenitors and SRC compared with SCF + FL alone or together with
IL-6 and soluble IL-6 receptor. IL6RIL6 chimera prolonged in vitro
maintenance of SRC for up to 14 days. Stimulation of
CD34+CD38 /low enriched cells with IL6RIL6
chimera maintained the early CD34+CD38/low
cell subpopulation, which could be detected in vitro for up to 14 days.
Moreover, IL6RIL6 chimera preferentially stimulated the growth of early
CD34+38/low cells, resulting in
significantly higher levels of progenitors compared with more
mature CD34+38+ cells. Taken together,
these findings demonstrate the importance of IL6RIL6 chimera in
stimulating the proliferation of early
CD34+· CD38gp130+IL-6R
cells in vitro and extended maintenance of progenitors and SRC.
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