Marrow-derived heparan sulfate proteoglycan mediates the adhesion of hematopoietic progenitor cells to cytokines

Abstract

Heparan sulfate proteoglycan (HS-PG), an important component of the human bone marrow extracellular matrix (ECM), is believed to influence hematopoietic progenitor cell development by binding and localizing growth factors to specific niches within the hematopoietic microenvironment. We utilized a model ECM system, which uses immobilized ECM proteins and/or cytokines and bone marrow populations enriched for human hematopoietic stem cell (HSC), to assess the effects of HS-PG on the development of primitive hematopoietic progenitor cells. HS-PG alone failed to bind hematopoietic progenitor cells cloned from bone marrow CD34+CD15-HLA-DR- cells, which are enriched for HSC. HS-PG alone failed to function as a mitogen. In sharp contrast, the interaction of HS-PG with either growth factors (interleukin-3 [IL-3] or stem cell factor/Kit ligand [KL] or an ECM protein (thrombospondin [TSP]) markedly influenced 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-forming unit-granulocyte/macrophage (CFU-GM), a 1.5-fold increase in attachment of the burst-forming unit-erythroid (BFU-E) and the high-proliferative-potential colony-forming cell (HPP-CFC), and a two- to three-fold increase in attachment of the colony-forming unit-granulocyte/erythroid/macrophage/megakaryocyte (CFU-GEMM) compared to localized growth 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 interacts with both growth factors and ECM proteins to augment progenitor cell localization within the hematopoietic microenvironment.