MARROW-DERIVED HEPARAN-SULFATE PROTEOGLYCAN MEDIATES THE ADHESION OF HEMATOPOIETIC PROGENITOR CELLS TO CYTOKINES

Heparan sulfate proteoglycan (HS-PG), an important component of the hu man bane marrow extracellular matrix (ECM), is believed to influence h ematopoietic progenitor cell development by binding and localizing gro wth factors to specific niches within the hematopoietic microenvironme nt. We utilized a model ECM system, which uses immobilized ECM protein s and/or cytokines and bone marrow populations enriched for human hema topoietic stem cells (HSC), to assess the effects of HS-PG on the deve lopment of primitive hematopoietic progenitor cells. HS-PG alone faile d to bind hematopoietic progenitor cells cloned from bone marrow CD34( +)CD15(-)HLA-DR(-) cells, which are enriched for HSC. HS-PG alone fail ed to function as a mitogen. In sharp contrast, the interaction of HS- PG with either growth factors (interleukin-3 [IL-3] or stem cell facto r/Kit ligand [KL]) or an ECM protein (thrombospondin [TSP]) markedly i nfluenced progenitor cell adherence. The binding of either IL-3 or KL to HS-PG resulted in a two-fold increase in attachment of the colony-f orming unit-granulocyte/macrophage (CFU-GM), a 1.5-fold increase in at tachment of the burst-forming unit-erythroid (BFU-E) and the high-prol iferative-potential colony-forming cell (HPP-CFC), and a two- to three -fold increase in attachment of the colony-forming nit-granulocyte/ery throid/macrophage/megakaryocyte (CFU-GEMM) compared to localized growt h factor alone. Attachment of the BFU-megakaryocyte (BFU-MK), however, was slightly reduced by the interaction of either IL-3 or KL with HS- PG. The interaction of HS-PG with TSP resulted in a two-fold increase in CFU-GM and CFU-GEMM attachment, while the attachment of BFU-E, HPP- CFC, and BFU-MK was unaltered. We conclude that HS-PG cooperatively in teracts with both growth factors and ECM proteins to augment progenito r cell localization within the hematopoietic microenvironment.