Mobilization of hematopoietic progenitor cells by yeast-derived beta-glucan requires activation of matrix metalloproteinase-9.
Poly-(1,6)-beta-d-glucopyranosyl-(1,3)-beta-d-glucopyranose (PGG) beta-glucan is a soluble yeast-derived polysaccharide that has previously been shown to induce hematopoietic progenitor cell (HPC) mobilization. However, the mobilizing mechanism of action remains unknown. Here, we confirmed that PGG beta-glucan alone or in combination with granulocyte colony-stimulating factor (G-CSF) mobilizes HPC into the periphery. Optimal mobilizing effects were seen 24-48 hours after PGG beta-glucan doses of 4.8-9.6 mg/kg. Animals treated with G-CSF and PGG beta-glucan showed a collaborative effect in HPC mobilization compared with G-CSF treatment alone. Additional studies demonstrated that neither complement 3 nor complement receptor 3 played a role in this effect and that PGG beta-glucan treatment did not induce proinflammatory cytokine secretion. However, bone marrow cells from PGG beta-glucan-treated mice secreted abundant matrix metalloproteinase-9 (MMP-9), and PGG beta-glucan-induced HPC mobilization was abrogated in MMP-9 knockout mice. Moreover, we demonstrated that both hematopoietic and nonhematopoietic cells contributed to MMP-9 secretion upon PGG beta-glucan treatment. In addition, HPCs mobilized by PGG beta-glucan had similar levels of engraftment in host and lineage differentiation capability compared with those mobilized by G-CSF. Thus, PGG beta-glucan is an agent that enhances HPC mobilization and may improve the outcome of clinical stem cell transplantation.
Cramer
Daniel E
DE
Tumor Immunobiology Program, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky 40202, USA.
Wagner
Stephanie
S
Li
Bing
B
Liu
Jingjing
J
Hansen
Richard
R
Reca
Ryan
R
Wu
Wan
W
Surma
Ewa Zuba
EZ
Laber
Damian A
DA
Ratajczak
Mariusz Z
MZ
Yan
Jun
J
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000097:blood; D003167:Complement Activation / Q000276:immunology; D003176:Complement C3 / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D018836:Inflammation Mediators; D016177:Macrophage-1 Antigen / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins; D012441:Saccharomyces cerevisiae / Q000737:chemistry*; D047071:beta-Glucans / Q000494:pharmacology*
D054377:Chemokine CXCL12; D003176:Complement C3; D016207:Cytokines; D018836:Inflammation Mediators; D016177:Macrophage-1 Antigen; D011994:Recombinant Proteins; D047071:beta-Glucans; C069894:poly-1-6-glucopyranosyl-1-3-glucopyranose glucan; D016179:Granulocyte Colony-Stimulating Factor; D020780:Matrix Metalloproteinase 9