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Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4641-4651
Structurally Specific Heparan Sulfates Support Primitive Human
Hematopoiesis by Formation of a Multimolecular Stem Cell Niche
Pankaj Gupta,
Theodore R. Oegema Jr,
Joseph J. Brazil,
Arkadiusz
Z. Dudek,
Arne Slungaard, and
Catherine M. Verfaillie
From the Departments of Medicine, Biochemistry, and Orthopædic
Surgery, VA Medical Center and University of Minnesota Medical School,
Minneapolis, MN.
Stem cell localization, conservation, and differentiation is
believed to occur in niches in the marrow stromal microenvironment. Our
recent observation that long-term in vitro human hematopoiesis requires
a stromal heparan sulfate proteoglycan (HSPG) led us to hypothesize
that such HSPG may orchestrate the formation of the stem cell niche. We
compared the structure and function of HS from M2-10B4, a
hematopoiesis-supportive cell line, with HS from a nonsupportive cell
line, FHS-173-We. Long-term culture-initiating cell (LTC-IC)
maintenance was enhanced by PG from supportive cells but not by PG from
nonsupportive cells (P < .005). The supportive HS were
significantly larger and more highly sulfated than the nonsupportive
HS. Specifically, supportive HS contained higher 6-O-sulfation on the
glucosamine residues. In agreement with these observations, purified
6-O-sulfated heparin and highly 6-O-sulfated bovine kidney HS similarly
maintained LTC-IC. In contrast, completely desulfated heparin,
N-sulfated heparin, and unmodified heparin did not support LTC-IC
maintenance. Moreover, the supportive HS promoted LTC-IC maintenance
but not differentiation of CD34+/HLA-DR
cells into colony-forming cells (CFCs) and mature blood
cells. The supportive HS but not the nonsupportive HS bound both
cytokines and matrix components critical for hematopoiesis, including
interleukin-3 (IL-3), macrophage inflammatory protein-1 (MIP-1),
and thrombospondin (TSP). Significantly more CD34+ cells
adhered directly to immobilized O-sulfated heparin than to N-sulfated
or desulfated heparin. Thus, hematopoiesis-supportive stromal HSPG
possessing large, highly 6-O-sulfated HS mediate the juxtaposition of
hematopoietic progenitors with stromal cells, specific growth-promoting
(IL-3) and growth-inhibitory (MIP-1 and platelet factor 4 [PF4])
cytokines, and extracellular matrix (ECM) proteins such as TSP. We
conclude that the structural specificity of stromal HSPG that
determines the selective colocalization of cytokines and ECM components
leads to the formation of discrete niches, thereby orchestrating the
controlled growth and differentiation of stem cells. These findings may
have important implications for ex vivo expansion of and gene transfer
into primitive hematopoietic progenitors.
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