Degradation of BM SDF-1 by MMP-9: the role in G-CSF-induced hematopoietic stem/progenitor cell mobilization.
The major involvement of chemokines and proteolytic enzymes has recently been discovered in the mobilization process. Here, we report that the degradation of BM stromal cell-derived factor (SDF-1) by matrix metalloproteinase (MMP)-9 is important in G-CSF-mediated hematopoietic stem/progenitor cells (HSPCs) mobilization. In this study, the SDF-1 concentration in healthy donors BM plasma decreased significantly after 5 days of G-CSF administration, with no obvious change of SDF-1 in the peripheral blood. We also observed a similar result by immunohistochemical staining on the BM biopsy slides. In vitro, mobilized BM plasma exhibited decreased chemotactic effect on CD34(+) cells, compared with steady-state BM plasma. MMP-9 protein and mRNA increased dramatically in the BM plasma in accordance with SDF-1 decrease. MMP-9 enriched supernatant from HT1080 cell-conditioned medium upregulated CXCR4 expression and the migration of BM CD34(+) cells toward SDF-1. SDF-1 was a substrate for MMP-9, furthermore, SDF-1 also stimulated MMP-9 proteolytic enzyme activity of BM CD34(+) cells, which facilitate HSPCs migration. In BALB/c mice, HSPCs mobilization was significantly inhibited by anti-SDF-1 antibodies or MMP inhibitor, o-phenanthroline. In conclusion, the degradation of BM SDF-1 by MMP-9 is a vital step in mobilization.
Jin
F
F
State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union of Medical College, Tianjin, China.
Zhai
Q
Q
Qiu
L
L
Meng
H
H
Zou
D
D
Wang
Y
Y
Li
Q
Q
Yu
Z
Z
Han
J
J
Li
Q
Q
Zhou
B
B
D000818:Animals; D018952:Antigens, CD34 / Q000097:blood; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D020780:Matrix Metalloproteinase 9 / Q000097:blood / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D018952:Antigens, CD34; D054377:Chemokine CXCL12; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D016179:Granulocyte Colony-Stimulating Factor; D020780:Matrix Metalloproteinase 9