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Blood, Vol. 95 No. 1 (January 1), 2000:
pp. 147-155
Human LTC-IC can be maintained for at least 5 weeks in vitro when
interleukin-3 and a single chemokine are combined with O-sulfated
heparan sulfates: requirement for optimal binding interactions of
heparan sulfate with early-acting cytokines and matrix proteins
Pankaj Gupta,
Theodore R. Oegema Jr,
Joseph J. Brazil,
Arkaduisz Z. Dudek,
Arne Slungaard, and
Catherine M. Verfaillie
From the Departments of Medicine and Orthopædic Surgery and
Biochemistry, Veterans Affairs Medical Center Minneapolis, MN, and
University of Minnesota, Minneapolis, MN.
We have shown that stromal O-sulfated heparan sulfate
glycosaminoglycans (O-S-GAGs) regulate primitive human hematopoietic progenitor cell (HPC) growth and differentiation by colocalizing heparin-binding cytokines and matrix proteins with HPC in stem cell
"niches" in the marrow microenvironment. We now show that long-term culture-initiating cells (LTC-IC) are maintained for 5 weeks
in the absence of stroma when O-S-GAGs are added to IL-3 and either
MIP-1 or PF4 (LTC-IC maintenance without GAGs, 32 ± 2%; with
GAGs, 95 ± 7%; P < .001). When cultured with 5 additional cytokines, O-S-GAGs, IL-3, and MIP-1, LTC-IC expanded 2- to 4-fold at 2 weeks, and 92 ± 8% LTC-IC were maintained at 5 weeks. Similar results were seen when PF4 replaced MIP-1. Although
O-S-GAG omission did not affect 2-week expansion, only 20% LTC-IC were
maintained for 5 weeks. When O-S-heparin was replaced by completely
desulfated-, N-sulfated (O-desulfated), or unmodified heparins, LTC-IC
maintenance at week 5 was not better than with cytokines alone.
Unmodified- and O-S-heparin, but not desulfated- or N-sulfated heparin,
bound to MIP-1, IL-3, PF4, VEGF, thrombospondin, and fibronectin.
However, the affinity of heparin for thrombospondin and PF4, and the
association and dissociation rates of heparin for PF4, were higher than
those of O-S-heparin. We conclude that (i) although cytokines may
suffice to induce early expansion, adult human LTC-IC maintenance for longer than 1 month requires O-S-GAGs, and (ii) HPC support may depend
not only on the ability of GAGs to bind proteins, but also on optimal
affinity and kinetics of interactions that affect presentation of
proteins in a biologically active manner to progenitors. (Blood. 2000;95:147-155)
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