Mobilization of Hematopoietic Progenitor Cells by Yeast-derived -Glucan Requires Activation of Matrix Metalloproteinase-9

¹ Tumor Immunobiology Program, James Graham Brown Cancer Center, Department of Medicine, University of Louisville
² Tumor Immunobiology Program, James Graham Brown Cancer Center, Department of Medicine, University of Louisville; Division of Hematology/Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville
³ Stem Cell Institute, James Graham Brown Cancer Center, Department of Medicine, University of Louisville
⁴ Division of Hematology/Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville

^* To whom correspondence should be addressed. E-mail: jun.yan{at}louisville.edu.

	Abstract

Poly-(1,6)--D-glucopyranosyl-(1,3)--D-glucopyranose (PGG) -glucan is a soluble yeast-derived polysaccharide that has been shown previously to induce hematopoietic progenitor cell (HPC) mobilization. However, the mobilizing mechanism of action remains unknown. Here, we confirmed that PGG -glucan alone or in combination with granulocyte colony-stimulating factor (G-CSF) mobilizes HPC into the periphery. Optimal mobilizing effects were seen 24 to 48 hours after PGG -glucan doses of 4.8-9.6 mg/kg. Animals treated with G-CSF and PGG -glucan showed a collaborative effect in HPC mobilization compared to G-CSF treatment alone. Further studies demonstrated that neither complement 3 (C3) nor C receptor 3 (CR3) played a role in this effect and that PGG -glucan treatment did not induce proinflammatory cytokine secretion. However, bone marrow (BM) cells from PGG -glucan-treated mice secreted abundant matrix metalloproteinase 9 (MMP-9) and PGG -glucan-induced HPC mobilization was abrogated in MMP-9 knockout mice. Moreover, we demonstrated that both hematopoietic and non-hematopoietic cells contributed to MMP-9 secretion upon PGG -glucan treatment. Additionally, HPCs mobilized by PGG -glucan had similar levels of engraftment in host and lineage differentiation capability compared to those mobilized by G-CSF. Thus, PGG -glucan is an agent that enhances HPC mobilization and may improve the outcome of clinical stem cell transplantation.

Key Words. Hematopoietic progenitor cells, mobilization, -glucan, matrix metalloproteinase-9